颞叶癫痫大鼠认知功能与突触重塑相关蛋白表达的研究
|
摘要
研究背景
癫痫是严重危害人类健康的慢性脑部疾病之一,癫痫发作易导致认知和行为异常,全世界目前约有5000万癫痫患者,给社会、家庭和个人都带来了沉重负担。颞叶癫痫(temporal lobe epilepsy,TLE)是癫痫发作中最常见的类型,自发性再发作(spontaneous recurrent seizure,SRS)是其特征,发作大多由颞叶及其附近的病变引起,临床上常表现为感觉、情绪、精神和运动等各种症状。由于颞叶癫痫的发作与海马等边缘系统的病变密切相关,而海马等又参与了记忆、学习、情绪、行为等认知功能的形成,所以,最近有关颞叶癫痫引起的认知功能障碍逐渐受到了人们的重视。认知功能是人类和动物的大脑高级神经活动,主要包括精神、智力活动的各个方面,如感觉、知觉、学习、记忆,其中最主要的是学习和记忆。学习、记忆的形成是十分复杂的,最近的研究表明,海马结构、突触的可塑性、抑制性氨基酸受体、钙离子、一氧化氮(nitrogen monoxidum,NO)等参与了学习与记忆的过程。一些与突触重塑相关的蛋白被认为是突触可塑性的主要调控者。目前,突触重塑相关蛋白在癫痫发作中的作用与机制已有少量报道,但是突触重塑相关蛋白在颞叶癫痫认知功能障碍中的作用和机制却不十分清楚,对颞叶癫痫认知功能障碍的预防和治疗也缺乏有效手段。
研究证实,海马是学习记忆的关键脑区,海马中的长时程增强(long-termpotentiation,LTP)现象被看作研究突触可塑性的理想模型,它与学习、记忆过程密切相关,可以作为“记忆的突触模型”或揭示“记忆的神经元机制”。N-甲基-D-门冬氨酸(N-methyl-D-aspartate,NMDA)受体属于兴奋性氨基酸-谷氨酸(glutamate,Glu)受体,被认为是突触可塑性及皮质和海马神经元LTP的主要调控者,构成了中枢神经系统的重要功能如学习和记忆的基础,其中NMDA 2型受体B亚基(NMDA receptor 2B subunit,NR2B)最为重要。NR2B主要分布在前脑区域如海马和纹状体,在中枢神经系统中广泛参与学习记忆、突触可塑性、神经发育、缺血性脑损伤、神经退行性变、癫痫、肿瘤等许多重要的生理病理过程。突触后致密物(postsynaptic density protein 95,PSD-95),又称SAP90(synapse associatedprotein 90),是在Glu能突触的突触后密集区发现的一种脚手架蛋白,是膜结合鸟苷酸激酶(guanylate kinas,GK)超家族的成员之一,因分子量为90-95kDa而命名。PSD-95由N端3个PDZ(Dlg,ZO-1/Dlg-homologous region)结构域,1个SH3(src homology 3)结构域和C端无活性的GK结构域组成,这些结构域可分别介导PSD-95家族蛋白质与特异性蛋白质的相互作用,其中PDZ结构域特异性地与NR2B的C端结合构成NR2B/PSD-95复合物,与缺血性中风、老龄化学习记忆障碍、抑郁、Alzhemer's disease(AD)、癫痫、亨廷顿病和精神分裂症等神经精神疾病密切相关。突触素(synaptophysin,Syp)是神经元和神经内分泌细胞突触囊泡膜上的一种分子量为38kDa的跨膜糖蛋白。Syp可能通过激活酪氨酸激酶(protein tyrosine kinase,PTK),使Syp磷酸化,从而调节内源性Glu的释放来影响突触可塑性,与AD、老龄化学习记忆障碍密切相关。实验证明LTP的诱导和Syp的合成是偶联的,如老年动物LTP和Syp合成同步减低。突触小体相关蛋白(synaptosomal-associated protein 25,SNAP-25)是SNARE(soluble N-ethylmaleimide-sensitive fusion protein(NSF)attachment protein receptor)蛋白超家族的一员,它与家族中另外两个成员syntaxin和synaptobrevin(也称为VAMP,vesicle-associatedmembrane protein)形成稳定的三元复合物,即SNARE复合体,在突触小泡的外排过程中发挥重要作用,直接介导了突触小泡膜与质膜的融合,为由钙离子引发的神经递质释放做好准备。SNAP-25在一系列神经过程中发挥重要作用,包括轴突生长、树突的形成、神经递质的释放和海马LTP的表达。实验证明SNAP-25在海马表达丰富,参与了学习、记忆过程。突触结合蛋白(synaptotagmin,Syt)是一类主要存在于神经及内分泌细胞分泌小泡膜的蛋白质,在哺乳动物已经被鉴定的有15种亚型,其中Syt 1含量最为丰富,能以钙依赖的方式与细胞膜结合,与神经递质释放密切相关。Syt 1分子由N端的跨膜结构域插入突触囊泡膜,胞浆中的C端分为C2A和C2B两个保守结构域,这两个结构域通常作为钙或者其他因子的结合位点,它在突触囊泡胞吐和胞吞两个过程中都发挥作用。目前已证明Syt 1是快速同步释放的Ca~(2+)感受器,并且执行此功能的区域主要在C2B区。此外,Syt 1能与SNARE蛋白的末梢受体结合,并且与囊泡内吞作用密切相关。Syt 1对阐明难治性神经疾患发病机制以及治疗等方面具有一定意义。最近研究发现,Syt 1与AD、老龄化学习记忆障碍密切相关。
到目前为止,海马区NR2B、PSD-95、Syp、SNP-25、Syt 1的表达与颞叶癫痫导致的认知功能障碍之间有何关系,仍未见报道。本研究建立红藻氨酸(kainicacid,KA)诱导的大鼠颞叶癫痫模型,检测颞叶癫痫大鼠认知功能的变化,应用组织学方法检测海马区神经元丢失坏死情况,利用免疫组化方法观察NR2B、PSD-95、Syp、SNP-25、Syt 1蛋白的表达,应用逆转录聚合酶链反应(reversetranscriptase polymerase chain reaction,RT-PCR)、Western blot检测NR2B、PSD-95、Syp、SNP-25、Syt 1 mRNA及蛋白的表达,探讨颞叶癫痫大鼠认知功能障碍发生的机制。本研究分为两部分:
第一部分颞叶癫痫大鼠认知损害与海马区synaptophysin、SNAP-25、synaptotagmin 1的异常表达
目的
评价KA诱导的大鼠颞叶癫痫模型认知功能损害;研究Syp、SNAP-25、Syt 1在颞叶癫痫认知功能障碍大鼠海马区的表达,探讨导致颞叶癫痫认知功能损害的可能分子机制。
方法
1.应用腹腔注射系统给药的方法建立KA诱导的大鼠癫痫模型。实验动物分为对照组、KA组,根据是否发展为SRS,KA组又分为颞叶癫痫组(KA+SRS组)、非颞叶癫痫组(KA-SRS组)。
2.应用行为学检测方法评价各组大鼠在致痫后6周(weeks,w)的认知功能。
3.应用HE、Nissl染色观察KA+SRS组、KA-SRS组大鼠在致痫后6w海马神经元的形态及数目改变。
4.应用免疫组织化学染色在电镜下观察各实验组大鼠在致痫后6w海马区Syp、SNAP-25、Syt 1的表达。
5.应用RT-PCR检测各组大鼠在致痫后6w海马区Syp、SNAP-25、Syt 1mRNA的表达。
6.应用Western blot检测各组大鼠在致痫后6w海马区Syp、SNAP-25、Syt1蛋白的表达。
结果
1.Morris水迷宫(Morris water maze)、高架十字迷宫(elevated-plus maze)、开场实验(Open field)检测显示,与对照组比较,KA-SRS组大鼠认知功能未见明显区别,KA+SRS组大鼠认知功能出现障碍(P＜0.05)。
2.对照组大鼠海马CA1、CA3、齿状回门区锥体细胞结构清晰完整,细胞核结构正常,染色质分布均匀,胞浆内尼氏小体丰富,未见明显神经元丢失坏死。KA+SRS组大鼠海马CA1、CA2、CA3、CA4及齿状回区未见广泛神经元丢失及胶质增生,可见局部神经元丢失和胶质增生。KA-SRS组大鼠海马未见明显神经元丢失。
3.Syp、SNAP-25、Syt 1免疫组化研究显示,对照组大鼠海马可见数目较多、深染的棕褐色Syp、SNAP-25、Syt 1阳性神经元,与对照组比较,KA-SRS组无明显差别,KA+SRS组Syp、SNAP-25阳性神经元数目明显较少、染色较浅,Syt1阳性神经元数目明显增多、染色较深。
4.RT-PCR研究显示,与对照组比较,KA-SRS组Syp、SNAP-25、Syt 1mRNA表达无明显差别,KA+SRS组Syp、SNAP-25 mRNA表达减弱(P＜0.05)、Syt 1mRNA表达无明显差别。
5.Western blot研究显示,与对照组比较,KA-SRS组Syp、SNAP-25、Syt1蛋白表达无明显差别,KA+SRS组Syp、SNAP-25蛋白表达减弱(P＜0.05),Syt1蛋白表达增强(P＜0.05)。
结论
1.颞叶癫痫长期反复发作可以导致认知功能障碍。
2.本实验中颞叶癫痫长期反复发作6w后未见广泛神经元丢失及胶质增生,可见局部神经元丢失和胶质增生。
3.颞叶癫痫长期反复发作可导致Syp、SNAP-25表达减弱、Syt 1表达增强,从而导致认知功能障碍。
第二部分颞叶癫痫大鼠认知功能变化与海马区NR2B/PSD-95动态表达的研究
目的
评价KA诱导的大鼠颞叶癫痫模型认知功能变化;研究NR2B/PSD-95在颞叶癫痫认知功能障碍大鼠海马区的动态表达及抗癫痫药物丙戊酸钠(valproic acid,VPA)对颞叶癫痫认知功能及海马区NR2B/PSD-95表达的影响,探讨导致颞叶癫痫认知功能障碍的可能分子机制。
方法
1.应用腹腔注射系统给药的方法建立KA诱导的大鼠颞叶癫痫模型。实验动物分为对照组、KA组、KA+VPA组,根据行为学检测时间,以上三个组再各自分为2w、4w、6w三个亚组。
2.应用行为学检测方法评价各亚组大鼠认知功能的变化。
3.应用Nissl染色观察KA组、KA+VPA组大鼠癫痫长期反复发作后6w海马神经元的形态及数目改变。
4.应用免疫组织化学染色在电镜下观察各亚组大鼠癫痫长期反复发作后海马区NR2B/PSD-95的动态表达。
5.应用RT-PCR观察各亚组大鼠癫痫长期反复发作后海马区NR2B/PSD-95mRNA的动态表达。
6.应用Western blot检测各亚组大鼠癫痫长期反复发作后海马区NR2B/PSD-95蛋白的动态表达。
结果
1.Morris水迷宫(Morris water maze)、高架十字迷宫(elevated-plus maze)、开场实验(Open field)检测显示KA-2w亚组、对照组及KA+VPA各亚组大鼠的认知功能未见明显区别,KA各亚组大鼠随时间的延长认知功能障碍逐渐加重(P＜0.05)。
2.NS-6w、KA+VPA-6w组大鼠海马CA1、CA3、齿状回门区锥体细胞结构清晰完整,细胞核结构正常,染色质分布均匀,胞浆内尼氏小体丰富,未见明显神经元丢失。KA-6w亚组大鼠海马CA1、CA2、CA3、CA4及齿状回区未见广泛神经元丢失及胶质增生,可见局部神经元丢失和胶质增生。
3.NR2B/PSD-95免疫组化研究显示,对照组大鼠海马可见数目较多、深染的棕褐色NR2B、PSD-95阳性神经元。与对照组比较,KA+VPA各亚组无明显差别,KA-6w亚组NR2B、PSD-95阳性神经元数目明显较少、染色较浅。
4.RT-PCR研究显示,KA-2w亚组、对照组及KA+VPA各亚组大鼠NR2B/PSD-95 mRNA的表达未见明显区别,KA各亚组大鼠随时间的延长NR2B/PSD-95 mRNA的表达逐渐减弱(P＜0.05)。
5.Western blot研究显示,KA-2w亚组、对照组及KA+VPA各亚组大鼠NR2B/PSD-95蛋白的表达未见明显区别,KA各亚组大鼠随时间的延长NR2B/PSD-95蛋白的表达逐渐减弱(P＜0.05)。
结论
1.颞叶癫痫大鼠长期反复发作可以导致认知功能障碍,且随时间延长逐渐加重。
2.本实验中颞叶癫痫长期反复发作6w后未见未见广泛神经元丢失及胶质增生,可见局部性神经元丢失和胶质增生。
3.颞叶癫痫长期反复发作可导致NR2B/PSD-95表达逐渐减弱,从而导致认知功能障碍。
4.VPA可以通过保护NR2B/PSD-95的表达,减轻颞叶癫痫长期反复发作导致的认知功能障碍。
研究意义
本研究应用KA制造大鼠颞叶癫痫模型,应用行为学方法检测颞叶癫痫导致的认知功能障碍,首次在成体动物水平证实突触重塑相关蛋白如NR2B、PSD-95、synaptophysin、SNAP-25、synaptotagmin 1参与颞叶癫痫发作导致的认知功能障碍,并同时证实了抗癫痫药物VPA可以通过保护NR2B/PSD-95的表达,减轻颞叶癫痫长期反复发作导致的认知功能障碍。本研究的结果从分子生物学水平上进一步阐明颞叶癫痫导致认知功能障碍的可能机制,有助于寻找新的药物作用靶点,研发新的改善颞叶癫痫认知功能障碍的药物。
Background
Epilepsy is one of the most common chronic neurological disorders affecting people of all ages, and it is prone to cause cognitive and neurobehavior impairment. At present, there are about 50 million of epilepsy patients worldwide. They suffer a lot from this disease and become big burdens to family and society. Temporal lobe epilepsy (TLE), the most common type of epilepsy in human, is characterized by spontaneous recurrent seizure (SRS), and is also be associated with memory impairment and behavioural problems, including depression, anxiety and psychoses. The clinical symptom of TLE is associated with aesthema, emotion, mind, and locomotion. SRS may be caused by lesion in hippocampus and other limbic system, and the hippocampal formation participates in the form of learning, memory, emotion, behavior and other cognitive function. Therefore, it is important to study the mechanism of cognitive impairment caused by SRS. The cognitive function belongs to higher nervous activity in human and animal, including every aspects of mind and intellect activity, which are aesthema, perception, learning and memory. It is very complicated to form learning and memory. Recent studies indicate that hippocampal formation, synaptic plasticity, inhibited amino acids receptor, calcium ion, nitrogen monoxidum (NO) all participate in the formation of learning and memory. A few of synaptic plasticity-related proteins are known as principal regulators in synaptic plasticity. Until now, only few studies report the mechanism underlying synaptic plasticity-related proteins in seizure activity. But the mechanism underlying synaptic plasticity-related proteins in behavioral deficits induced by SRS is still unclear. Moreover, there are still limited strategies to protect cognitive impairment induce by SRS.
Some studies confirm that the hippocampus is important encephalic region, which plays a central role in learning and memory. Long-term potentiation (LTP) in the hippocampus is regarded as an ideal model to study synaptic plasticity, also as "a synaptic model of memory" or "neuronal mechanism of memory". The NMDA receptor, one of excitatory amino acids receptors—glumatic acid receptor, is known as a principal regulator in synaptic plasticity and LTP in hippocampus and cortex. The NR2B subunit, which is expressed at its highest levels in the olfactory tubercle, hippocampus, olfactory bulb, and cerebral cortex, has been implicated as a principal player in learning, memory, synaptic plasticity, neural development, ischemic brain injure, neurodegeneration, epilepsy and tumor. PSD-95 (postsynaptic density protein 95), i.e. SAP90 (synapse associated protein 90), is a scaffold protein and one of guanylate kinase superfamily exclusively localized to glutamatergic synapses and is characterized by three PDZ (Dlg, ZO-1/Dlg-homologous region) domains, a SH3 (SRC Homology 3) domain and a GK (Guanylate kinase-like) domain. The PDZ domains of PSD-95 specifically bind to the C terminus of the NR2B subunit. It has been shown that the complex of NR2B and PSD-95 plays an important role in several neurodegenerative diseases, such as ischemic stroke, aged-learning deficits, depression, Alzhemer's disease (AD), epilepsy, Huntington disease and schizophrenia. Synaptophysin (Syp) is a 38-kDa calcium-binding glycoprotein found in the membranes of neurotransmitter-containing presynaptic vesicles. Syp may regulate release of endogenous glumatic acid to influence synaptic plasticity through phosphorylation after protein tyrosine kinase (PTK) activation. As the loss of synaptic marker, it is better parameter that correlates with memory dysfunction in AD and age-related memory. One study also indicates that induction of LTP and synthesis of Syp may be link-coupled. For example, LTP and Syp in old age animal is synchronously decreased. Together with other proteins including the synaptic vesicle protein VAMP (vesicle associated membrane protein, also called synaptobrevin) or the plasma membrane protein syntaxin (also HPC-1), SNAP-25 (synaptosomal-associated protein of 25 kDa) forms the so-called SNARE (soluble Nethylmaleimide-sensitive factor attachment receptor) protein complex. SNAP-25 is an integral component of the synaptic vesicle-docking/fusion core complex and plays an essential role in exocytosis/release of neurotransmitter. It plays a critical role in axon growth, dendric formation, neurotransmitter release and expression of hippocampal LTP. Recent study suggests SNAP-25 is highly expressed by neurons in hippocampus and play a major role in learning and memory. Synaptotagmin (Syt) is a protein located principally in secretory vesicle membrane of neuron and endocrine cell. There are 16 subtypes identified in mammal, and Syt 1 is the most abundant in hippocampus. As a calmodulin, Syt 1 binds to cellular membrane by calcium-dependent way and correlates intimately with release of neurotransmitter. Syt 1 inserts synaptic vesicle membrane by membrane spaning domain at N terminus. Syt 1 possesses two C2 domains, C2A and C2B, both being capable of calcium-dependent phospholipid binding in in vitro reactions. According to the available data, Syt 1 is a promoter of the synaptic vesicle fusion, mainly functioning as a fast calcium sensor for synchronous release of neurotransmitter via facilitating exocytosis and endocytosis. Now, some studies demonstrate that Syt 1 may act as a calcium sensor to mediate stimulus-coupled fast chemical synaptic transmission, and the domain carrying out the function is C2B. In addition, Syt 1 may bind to SNARE protein receptor. Syt 1 is important to elucidate the pathogenesy and therapy of refractory nerver diseases. Recent studies suggest that Syt 1 correlates with AD and aged-memory deficits.
To our knowledge, the role of NR2B, PSD-95, Syp, SNP-25, Syt 1 has not been studied in TLE animal model with behavior deficits. Thus, in this study we try to investigate whether SRS might decrease expression of NR2B, PSD-95, Syp, SNP-25, Syt 1 and consequently cause behavior deficits in rats with SRS induced by kainic acid (KA). Therefore, part of the molecular mechanism of cognitive impairment might be revealed.
PartⅠThe cognitive impairment in temporal lobe epilepsy rats and the abnormal expression of synaptophysin, SNAP-25,synaptotagmin 1 in the hippocampus.
Objective
To evaluate cognitive impairment in TLE rats induced by KA, investigate the expression of Syp, SNAP-25, Syt 1 in the hippocampus of rats with behavior deficits, and explore the partly possible molecular mechanism of cognitive impairment caused by TLE.
Method
1. Seizures were induced by KA through intraperitoneal injection. Rats were randomly divided into control group, KA group. Next, according to whether to develop SRS, KA group rats were divided into KA+SRS group and KA-SRS group.
2. To evaluate cognitive function in every experiment groups by behavior tests.
3. To evaluate pathology features of hippocampal neurons of KA+SRS and KA-SRS groups at 6w. Haematoxylin & Eosin staining and Nissl staining by Toluidine Blue were performed.
4. Immunohistochemistry staining was used to detect expression of Syp, SNAP-25, Syt 1 proteins at different experiment groups by electron microscope.
5. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to detect expression of Syp, SNAP-25, Syt 1 mRNA at different experiment groups.
6. Western blot analysis was used to detect expression alterations of Syp, SNAP-25, Syt 1 proteins at different experiment groups.
Result
1. Morris water maze, elevated-plus maze and open field analyses showed the cognitive function of KA+SRS group became worse (P<0.05), when compared with control or KA-SRS group.
2. No extensive destruction was noted in the dentate gyrus, CA1 and CA3 subfields of hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of KA+SRS group rats.
3. Immunohistochemistry staining of Syp, SNAP-25, Syt 1 showed there were lots of trachychromatic brown Syp, SNAP-25, Syt 1 positive neurons in control group rats. Compared with Syp, SNAP-25, Syt 1 positive neurons in control group, those of KA+SRS group were fewer and shallower. But there was no significant difference between control group and KA-SRS group.
4. RT-PCR analysis showed that expression of Syp, SNAP-25 mRNA in KA+SRS group were decreased (P<0.05), and expression of Syt 1 mRNA in KA+SRS group was not significantly changed, when compared with those in control or KA-SRS group.
5. Western blot analysis showed that expression of Syp, SNAP-25, Syt 1 protein in KA+SRS group were decreased (P<0.05), when compared with those in control or KA-SRS group.
Conclusion
1. SRS induced by KA may lead to cognitive impairment.
2. At the present experiment, no extensive destruction was noted in hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of rats with SRS.
3. SRS induced by KA may decrease Syp and SNAP-25 expression, and increase Syt 1 expression, consequently cause cognitive impairment.
PartⅡThe evaluation of cognitive function in temporal lobe epilepsy rats and the expression of NR2B/PSD-95 with time in the hippocampus
Objective
To evaluate cognitive function in TLE rats induced by KA, investigate the alterations of NR2B/PSD-95 in the hippocampus of rats with behavior deficits with time, investigate the role of antiepileptic VPA for cognitive function and expression of NR2B/PSD-95 in the hippocampus, and explore the possible molecular mechanism of cognitive impairment caused by SRS.
Method
1. SRS were induced by KA through intraperitoneal injection. Rats were randomly divided into control group, KA group and KA+VPA group. Next, according to the time point of behavioral tests, the above three groups were randomly divided into 2 w, 4w and 6w subgroups, respectively.
2. To evaluate cognitive function in every experiment subgroups by behavioral tests.
3. To evaluate pathology features of hippocampal neurons of KA and KA+VPA subgroups at 6w. Nissl staining by Toluidine Blue were performed.
4. Immunohistochemistry staining was used to detect expression of NR2B and PSD-95 proteins with time at different experiment subgroups by electron microscope.
5. RT-PCR analysis was used to detect alterations of NR2B and PSD-95 mRNA with time at different experiment subgroups.
6. Western blot analysis was used to detect alterations of NR2B and PSD-95 proteins with time at different experiment subgroups.
Result
1. Morris water maze, elevated-plus maze and open field analyses showed the cognitive impairment in three KA subgroups gradually became more serious with time (P<0.05), while there was no difference among KA-2w, control and KA+VPA subgroups at any time.
2. No extensive destruction was noted in the dentate gyrus, CA1 and CA3 subfields of hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of KA-6w subgroup rats.
3. Immunohistochemistry staining of NR2B and PSD-95 showed there were lots of trachychromatic brown NR2B and PSD-95 positive neurons in control group rats. Compared with NR2B and PSD-95 positive neurons in control group, those in KA-6w subgroup were fewer and shallower. But there was no significant difference between control subgroup and KA+VPA subgroup at any time.
4. RT-PCR analysis showed that expression of NR2B and PSD-95 mRNA in three KA subgroups were gradually down-regulated (P<0.05), while there was no difference among KA-2w, control and KA+VPA subgroups at any time.
5. Western blot analysis showed that expression of NR2B and PSD-95 protein in three KA subgroups were gradually down-regulated (P<0.05), while there was no difference among KA-2w, control and KA+VPA subgroups at any time.
Conclusion
1. SRS induced by KA may lead to cognitive impairment, which gradually become more serious with time.
2. At the present experiment, no extensive destruction was noted in hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of KA-6w subgroup.
3. SRS induced by KA may decrease NR2B and PSD-95 expression, and consequently cause cognitive impairment.
4. VPA might improve cognitive impairment by maintain NR2B and PSD-95 expression.
Significance
Using a rodent TLE model induced by KA and evaluating behavioral deficits caused by SRS, we investigated and confirmed that synaptic plasticity-related proteins, such as NR2B, PSD-95, synaptophysin, SNAP-25, synaptotagmin 1 played an important role in cognitive impairment caused by SRS. Furthermore, we showed that VPA might improve cognitive impairment by maintain NR2B and PSD-95 expression. Studies on synaptic plasticity-related proteins will undoubtedly help us to know more about the possible mechamism of behavioral deficits caused by SRS. Thus, this study may provide new insights into therapeutic target and develop new neuroprotective drug improving cognitive impairment.
癫痫是严重危害人类健康的慢性脑部疾病之一,癫痫发作易导致认知和行为异常,全世界目前约有5000万癫痫患者,给社会、家庭和个人都带来了沉重负担。颞叶癫痫(temporal lobe epilepsy,TLE)是癫痫发作中最常见的类型,自发性再发作(spontaneous recurrent seizure,SRS)是其特征,发作大多由颞叶及其附近的病变引起,临床上常表现为感觉、情绪、精神和运动等各种症状。由于颞叶癫痫的发作与海马等边缘系统的病变密切相关,而海马等又参与了记忆、学习、情绪、行为等认知功能的形成,所以,最近有关颞叶癫痫引起的认知功能障碍逐渐受到了人们的重视。认知功能是人类和动物的大脑高级神经活动,主要包括精神、智力活动的各个方面,如感觉、知觉、学习、记忆,其中最主要的是学习和记忆。学习、记忆的形成是十分复杂的,最近的研究表明,海马结构、突触的可塑性、抑制性氨基酸受体、钙离子、一氧化氮(nitrogen monoxidum,NO)等参与了学习与记忆的过程。一些与突触重塑相关的蛋白被认为是突触可塑性的主要调控者。目前,突触重塑相关蛋白在癫痫发作中的作用与机制已有少量报道,但是突触重塑相关蛋白在颞叶癫痫认知功能障碍中的作用和机制却不十分清楚,对颞叶癫痫认知功能障碍的预防和治疗也缺乏有效手段。
研究证实,海马是学习记忆的关键脑区,海马中的长时程增强(long-termpotentiation,LTP)现象被看作研究突触可塑性的理想模型,它与学习、记忆过程密切相关,可以作为“记忆的突触模型”或揭示“记忆的神经元机制”。N-甲基-D-门冬氨酸(N-methyl-D-aspartate,NMDA)受体属于兴奋性氨基酸-谷氨酸(glutamate,Glu)受体,被认为是突触可塑性及皮质和海马神经元LTP的主要调控者,构成了中枢神经系统的重要功能如学习和记忆的基础,其中NMDA 2型受体B亚基(NMDA receptor 2B subunit,NR2B)最为重要。NR2B主要分布在前脑区域如海马和纹状体,在中枢神经系统中广泛参与学习记忆、突触可塑性、神经发育、缺血性脑损伤、神经退行性变、癫痫、肿瘤等许多重要的生理病理过程。突触后致密物(postsynaptic density protein 95,PSD-95),又称SAP90(synapse associatedprotein 90),是在Glu能突触的突触后密集区发现的一种脚手架蛋白,是膜结合鸟苷酸激酶(guanylate kinas,GK)超家族的成员之一,因分子量为90-95kDa而命名。PSD-95由N端3个PDZ(Dlg,ZO-1/Dlg-homologous region)结构域,1个SH3(src homology 3)结构域和C端无活性的GK结构域组成,这些结构域可分别介导PSD-95家族蛋白质与特异性蛋白质的相互作用,其中PDZ结构域特异性地与NR2B的C端结合构成NR2B/PSD-95复合物,与缺血性中风、老龄化学习记忆障碍、抑郁、Alzhemer's disease(AD)、癫痫、亨廷顿病和精神分裂症等神经精神疾病密切相关。突触素(synaptophysin,Syp)是神经元和神经内分泌细胞突触囊泡膜上的一种分子量为38kDa的跨膜糖蛋白。Syp可能通过激活酪氨酸激酶(protein tyrosine kinase,PTK),使Syp磷酸化,从而调节内源性Glu的释放来影响突触可塑性,与AD、老龄化学习记忆障碍密切相关。实验证明LTP的诱导和Syp的合成是偶联的,如老年动物LTP和Syp合成同步减低。突触小体相关蛋白(synaptosomal-associated protein 25,SNAP-25)是SNARE(soluble N-ethylmaleimide-sensitive fusion protein(NSF)attachment protein receptor)蛋白超家族的一员,它与家族中另外两个成员syntaxin和synaptobrevin(也称为VAMP,vesicle-associatedmembrane protein)形成稳定的三元复合物,即SNARE复合体,在突触小泡的外排过程中发挥重要作用,直接介导了突触小泡膜与质膜的融合,为由钙离子引发的神经递质释放做好准备。SNAP-25在一系列神经过程中发挥重要作用,包括轴突生长、树突的形成、神经递质的释放和海马LTP的表达。实验证明SNAP-25在海马表达丰富,参与了学习、记忆过程。突触结合蛋白(synaptotagmin,Syt)是一类主要存在于神经及内分泌细胞分泌小泡膜的蛋白质,在哺乳动物已经被鉴定的有15种亚型,其中Syt 1含量最为丰富,能以钙依赖的方式与细胞膜结合,与神经递质释放密切相关。Syt 1分子由N端的跨膜结构域插入突触囊泡膜,胞浆中的C端分为C2A和C2B两个保守结构域,这两个结构域通常作为钙或者其他因子的结合位点,它在突触囊泡胞吐和胞吞两个过程中都发挥作用。目前已证明Syt 1是快速同步释放的Ca~(2+)感受器,并且执行此功能的区域主要在C2B区。此外,Syt 1能与SNARE蛋白的末梢受体结合,并且与囊泡内吞作用密切相关。Syt 1对阐明难治性神经疾患发病机制以及治疗等方面具有一定意义。最近研究发现,Syt 1与AD、老龄化学习记忆障碍密切相关。
到目前为止,海马区NR2B、PSD-95、Syp、SNP-25、Syt 1的表达与颞叶癫痫导致的认知功能障碍之间有何关系,仍未见报道。本研究建立红藻氨酸(kainicacid,KA)诱导的大鼠颞叶癫痫模型,检测颞叶癫痫大鼠认知功能的变化,应用组织学方法检测海马区神经元丢失坏死情况,利用免疫组化方法观察NR2B、PSD-95、Syp、SNP-25、Syt 1蛋白的表达,应用逆转录聚合酶链反应(reversetranscriptase polymerase chain reaction,RT-PCR)、Western blot检测NR2B、PSD-95、Syp、SNP-25、Syt 1 mRNA及蛋白的表达,探讨颞叶癫痫大鼠认知功能障碍发生的机制。本研究分为两部分:
第一部分颞叶癫痫大鼠认知损害与海马区synaptophysin、SNAP-25、synaptotagmin 1的异常表达
目的
评价KA诱导的大鼠颞叶癫痫模型认知功能损害;研究Syp、SNAP-25、Syt 1在颞叶癫痫认知功能障碍大鼠海马区的表达,探讨导致颞叶癫痫认知功能损害的可能分子机制。
方法
1.应用腹腔注射系统给药的方法建立KA诱导的大鼠癫痫模型。实验动物分为对照组、KA组,根据是否发展为SRS,KA组又分为颞叶癫痫组(KA+SRS组)、非颞叶癫痫组(KA-SRS组)。
2.应用行为学检测方法评价各组大鼠在致痫后6周(weeks,w)的认知功能。
3.应用HE、Nissl染色观察KA+SRS组、KA-SRS组大鼠在致痫后6w海马神经元的形态及数目改变。
4.应用免疫组织化学染色在电镜下观察各实验组大鼠在致痫后6w海马区Syp、SNAP-25、Syt 1的表达。
5.应用RT-PCR检测各组大鼠在致痫后6w海马区Syp、SNAP-25、Syt 1mRNA的表达。
6.应用Western blot检测各组大鼠在致痫后6w海马区Syp、SNAP-25、Syt1蛋白的表达。
结果
1.Morris水迷宫(Morris water maze)、高架十字迷宫(elevated-plus maze)、开场实验(Open field)检测显示,与对照组比较,KA-SRS组大鼠认知功能未见明显区别,KA+SRS组大鼠认知功能出现障碍(P＜0.05)。
2.对照组大鼠海马CA1、CA3、齿状回门区锥体细胞结构清晰完整,细胞核结构正常,染色质分布均匀,胞浆内尼氏小体丰富,未见明显神经元丢失坏死。KA+SRS组大鼠海马CA1、CA2、CA3、CA4及齿状回区未见广泛神经元丢失及胶质增生,可见局部神经元丢失和胶质增生。KA-SRS组大鼠海马未见明显神经元丢失。
3.Syp、SNAP-25、Syt 1免疫组化研究显示,对照组大鼠海马可见数目较多、深染的棕褐色Syp、SNAP-25、Syt 1阳性神经元,与对照组比较,KA-SRS组无明显差别,KA+SRS组Syp、SNAP-25阳性神经元数目明显较少、染色较浅,Syt1阳性神经元数目明显增多、染色较深。
4.RT-PCR研究显示,与对照组比较,KA-SRS组Syp、SNAP-25、Syt 1mRNA表达无明显差别,KA+SRS组Syp、SNAP-25 mRNA表达减弱(P＜0.05)、Syt 1mRNA表达无明显差别。
5.Western blot研究显示,与对照组比较,KA-SRS组Syp、SNAP-25、Syt1蛋白表达无明显差别,KA+SRS组Syp、SNAP-25蛋白表达减弱(P＜0.05),Syt1蛋白表达增强(P＜0.05)。
结论
1.颞叶癫痫长期反复发作可以导致认知功能障碍。
2.本实验中颞叶癫痫长期反复发作6w后未见广泛神经元丢失及胶质增生,可见局部神经元丢失和胶质增生。
3.颞叶癫痫长期反复发作可导致Syp、SNAP-25表达减弱、Syt 1表达增强,从而导致认知功能障碍。
第二部分颞叶癫痫大鼠认知功能变化与海马区NR2B/PSD-95动态表达的研究
目的
评价KA诱导的大鼠颞叶癫痫模型认知功能变化;研究NR2B/PSD-95在颞叶癫痫认知功能障碍大鼠海马区的动态表达及抗癫痫药物丙戊酸钠(valproic acid,VPA)对颞叶癫痫认知功能及海马区NR2B/PSD-95表达的影响,探讨导致颞叶癫痫认知功能障碍的可能分子机制。
方法
1.应用腹腔注射系统给药的方法建立KA诱导的大鼠颞叶癫痫模型。实验动物分为对照组、KA组、KA+VPA组,根据行为学检测时间,以上三个组再各自分为2w、4w、6w三个亚组。
2.应用行为学检测方法评价各亚组大鼠认知功能的变化。
3.应用Nissl染色观察KA组、KA+VPA组大鼠癫痫长期反复发作后6w海马神经元的形态及数目改变。
4.应用免疫组织化学染色在电镜下观察各亚组大鼠癫痫长期反复发作后海马区NR2B/PSD-95的动态表达。
5.应用RT-PCR观察各亚组大鼠癫痫长期反复发作后海马区NR2B/PSD-95mRNA的动态表达。
6.应用Western blot检测各亚组大鼠癫痫长期反复发作后海马区NR2B/PSD-95蛋白的动态表达。
结果
1.Morris水迷宫(Morris water maze)、高架十字迷宫(elevated-plus maze)、开场实验(Open field)检测显示KA-2w亚组、对照组及KA+VPA各亚组大鼠的认知功能未见明显区别,KA各亚组大鼠随时间的延长认知功能障碍逐渐加重(P＜0.05)。
2.NS-6w、KA+VPA-6w组大鼠海马CA1、CA3、齿状回门区锥体细胞结构清晰完整,细胞核结构正常,染色质分布均匀,胞浆内尼氏小体丰富,未见明显神经元丢失。KA-6w亚组大鼠海马CA1、CA2、CA3、CA4及齿状回区未见广泛神经元丢失及胶质增生,可见局部神经元丢失和胶质增生。
3.NR2B/PSD-95免疫组化研究显示,对照组大鼠海马可见数目较多、深染的棕褐色NR2B、PSD-95阳性神经元。与对照组比较,KA+VPA各亚组无明显差别,KA-6w亚组NR2B、PSD-95阳性神经元数目明显较少、染色较浅。
4.RT-PCR研究显示,KA-2w亚组、对照组及KA+VPA各亚组大鼠NR2B/PSD-95 mRNA的表达未见明显区别,KA各亚组大鼠随时间的延长NR2B/PSD-95 mRNA的表达逐渐减弱(P＜0.05)。
5.Western blot研究显示,KA-2w亚组、对照组及KA+VPA各亚组大鼠NR2B/PSD-95蛋白的表达未见明显区别,KA各亚组大鼠随时间的延长NR2B/PSD-95蛋白的表达逐渐减弱(P＜0.05)。
结论
1.颞叶癫痫大鼠长期反复发作可以导致认知功能障碍,且随时间延长逐渐加重。
2.本实验中颞叶癫痫长期反复发作6w后未见未见广泛神经元丢失及胶质增生,可见局部性神经元丢失和胶质增生。
3.颞叶癫痫长期反复发作可导致NR2B/PSD-95表达逐渐减弱,从而导致认知功能障碍。
4.VPA可以通过保护NR2B/PSD-95的表达,减轻颞叶癫痫长期反复发作导致的认知功能障碍。
研究意义
本研究应用KA制造大鼠颞叶癫痫模型,应用行为学方法检测颞叶癫痫导致的认知功能障碍,首次在成体动物水平证实突触重塑相关蛋白如NR2B、PSD-95、synaptophysin、SNAP-25、synaptotagmin 1参与颞叶癫痫发作导致的认知功能障碍,并同时证实了抗癫痫药物VPA可以通过保护NR2B/PSD-95的表达,减轻颞叶癫痫长期反复发作导致的认知功能障碍。本研究的结果从分子生物学水平上进一步阐明颞叶癫痫导致认知功能障碍的可能机制,有助于寻找新的药物作用靶点,研发新的改善颞叶癫痫认知功能障碍的药物。
Background
Epilepsy is one of the most common chronic neurological disorders affecting people of all ages, and it is prone to cause cognitive and neurobehavior impairment. At present, there are about 50 million of epilepsy patients worldwide. They suffer a lot from this disease and become big burdens to family and society. Temporal lobe epilepsy (TLE), the most common type of epilepsy in human, is characterized by spontaneous recurrent seizure (SRS), and is also be associated with memory impairment and behavioural problems, including depression, anxiety and psychoses. The clinical symptom of TLE is associated with aesthema, emotion, mind, and locomotion. SRS may be caused by lesion in hippocampus and other limbic system, and the hippocampal formation participates in the form of learning, memory, emotion, behavior and other cognitive function. Therefore, it is important to study the mechanism of cognitive impairment caused by SRS. The cognitive function belongs to higher nervous activity in human and animal, including every aspects of mind and intellect activity, which are aesthema, perception, learning and memory. It is very complicated to form learning and memory. Recent studies indicate that hippocampal formation, synaptic plasticity, inhibited amino acids receptor, calcium ion, nitrogen monoxidum (NO) all participate in the formation of learning and memory. A few of synaptic plasticity-related proteins are known as principal regulators in synaptic plasticity. Until now, only few studies report the mechanism underlying synaptic plasticity-related proteins in seizure activity. But the mechanism underlying synaptic plasticity-related proteins in behavioral deficits induced by SRS is still unclear. Moreover, there are still limited strategies to protect cognitive impairment induce by SRS.
Some studies confirm that the hippocampus is important encephalic region, which plays a central role in learning and memory. Long-term potentiation (LTP) in the hippocampus is regarded as an ideal model to study synaptic plasticity, also as "a synaptic model of memory" or "neuronal mechanism of memory". The NMDA receptor, one of excitatory amino acids receptors—glumatic acid receptor, is known as a principal regulator in synaptic plasticity and LTP in hippocampus and cortex. The NR2B subunit, which is expressed at its highest levels in the olfactory tubercle, hippocampus, olfactory bulb, and cerebral cortex, has been implicated as a principal player in learning, memory, synaptic plasticity, neural development, ischemic brain injure, neurodegeneration, epilepsy and tumor. PSD-95 (postsynaptic density protein 95), i.e. SAP90 (synapse associated protein 90), is a scaffold protein and one of guanylate kinase superfamily exclusively localized to glutamatergic synapses and is characterized by three PDZ (Dlg, ZO-1/Dlg-homologous region) domains, a SH3 (SRC Homology 3) domain and a GK (Guanylate kinase-like) domain. The PDZ domains of PSD-95 specifically bind to the C terminus of the NR2B subunit. It has been shown that the complex of NR2B and PSD-95 plays an important role in several neurodegenerative diseases, such as ischemic stroke, aged-learning deficits, depression, Alzhemer's disease (AD), epilepsy, Huntington disease and schizophrenia. Synaptophysin (Syp) is a 38-kDa calcium-binding glycoprotein found in the membranes of neurotransmitter-containing presynaptic vesicles. Syp may regulate release of endogenous glumatic acid to influence synaptic plasticity through phosphorylation after protein tyrosine kinase (PTK) activation. As the loss of synaptic marker, it is better parameter that correlates with memory dysfunction in AD and age-related memory. One study also indicates that induction of LTP and synthesis of Syp may be link-coupled. For example, LTP and Syp in old age animal is synchronously decreased. Together with other proteins including the synaptic vesicle protein VAMP (vesicle associated membrane protein, also called synaptobrevin) or the plasma membrane protein syntaxin (also HPC-1), SNAP-25 (synaptosomal-associated protein of 25 kDa) forms the so-called SNARE (soluble Nethylmaleimide-sensitive factor attachment receptor) protein complex. SNAP-25 is an integral component of the synaptic vesicle-docking/fusion core complex and plays an essential role in exocytosis/release of neurotransmitter. It plays a critical role in axon growth, dendric formation, neurotransmitter release and expression of hippocampal LTP. Recent study suggests SNAP-25 is highly expressed by neurons in hippocampus and play a major role in learning and memory. Synaptotagmin (Syt) is a protein located principally in secretory vesicle membrane of neuron and endocrine cell. There are 16 subtypes identified in mammal, and Syt 1 is the most abundant in hippocampus. As a calmodulin, Syt 1 binds to cellular membrane by calcium-dependent way and correlates intimately with release of neurotransmitter. Syt 1 inserts synaptic vesicle membrane by membrane spaning domain at N terminus. Syt 1 possesses two C2 domains, C2A and C2B, both being capable of calcium-dependent phospholipid binding in in vitro reactions. According to the available data, Syt 1 is a promoter of the synaptic vesicle fusion, mainly functioning as a fast calcium sensor for synchronous release of neurotransmitter via facilitating exocytosis and endocytosis. Now, some studies demonstrate that Syt 1 may act as a calcium sensor to mediate stimulus-coupled fast chemical synaptic transmission, and the domain carrying out the function is C2B. In addition, Syt 1 may bind to SNARE protein receptor. Syt 1 is important to elucidate the pathogenesy and therapy of refractory nerver diseases. Recent studies suggest that Syt 1 correlates with AD and aged-memory deficits.
To our knowledge, the role of NR2B, PSD-95, Syp, SNP-25, Syt 1 has not been studied in TLE animal model with behavior deficits. Thus, in this study we try to investigate whether SRS might decrease expression of NR2B, PSD-95, Syp, SNP-25, Syt 1 and consequently cause behavior deficits in rats with SRS induced by kainic acid (KA). Therefore, part of the molecular mechanism of cognitive impairment might be revealed.
PartⅠThe cognitive impairment in temporal lobe epilepsy rats and the abnormal expression of synaptophysin, SNAP-25,synaptotagmin 1 in the hippocampus.
Objective
To evaluate cognitive impairment in TLE rats induced by KA, investigate the expression of Syp, SNAP-25, Syt 1 in the hippocampus of rats with behavior deficits, and explore the partly possible molecular mechanism of cognitive impairment caused by TLE.
Method
1. Seizures were induced by KA through intraperitoneal injection. Rats were randomly divided into control group, KA group. Next, according to whether to develop SRS, KA group rats were divided into KA+SRS group and KA-SRS group.
2. To evaluate cognitive function in every experiment groups by behavior tests.
3. To evaluate pathology features of hippocampal neurons of KA+SRS and KA-SRS groups at 6w. Haematoxylin & Eosin staining and Nissl staining by Toluidine Blue were performed.
4. Immunohistochemistry staining was used to detect expression of Syp, SNAP-25, Syt 1 proteins at different experiment groups by electron microscope.
5. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to detect expression of Syp, SNAP-25, Syt 1 mRNA at different experiment groups.
6. Western blot analysis was used to detect expression alterations of Syp, SNAP-25, Syt 1 proteins at different experiment groups.
Result
1. Morris water maze, elevated-plus maze and open field analyses showed the cognitive function of KA+SRS group became worse (P<0.05), when compared with control or KA-SRS group.
2. No extensive destruction was noted in the dentate gyrus, CA1 and CA3 subfields of hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of KA+SRS group rats.
3. Immunohistochemistry staining of Syp, SNAP-25, Syt 1 showed there were lots of trachychromatic brown Syp, SNAP-25, Syt 1 positive neurons in control group rats. Compared with Syp, SNAP-25, Syt 1 positive neurons in control group, those of KA+SRS group were fewer and shallower. But there was no significant difference between control group and KA-SRS group.
4. RT-PCR analysis showed that expression of Syp, SNAP-25 mRNA in KA+SRS group were decreased (P<0.05), and expression of Syt 1 mRNA in KA+SRS group was not significantly changed, when compared with those in control or KA-SRS group.
5. Western blot analysis showed that expression of Syp, SNAP-25, Syt 1 protein in KA+SRS group were decreased (P<0.05), when compared with those in control or KA-SRS group.
Conclusion
1. SRS induced by KA may lead to cognitive impairment.
2. At the present experiment, no extensive destruction was noted in hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of rats with SRS.
3. SRS induced by KA may decrease Syp and SNAP-25 expression, and increase Syt 1 expression, consequently cause cognitive impairment.
PartⅡThe evaluation of cognitive function in temporal lobe epilepsy rats and the expression of NR2B/PSD-95 with time in the hippocampus
Objective
To evaluate cognitive function in TLE rats induced by KA, investigate the alterations of NR2B/PSD-95 in the hippocampus of rats with behavior deficits with time, investigate the role of antiepileptic VPA for cognitive function and expression of NR2B/PSD-95 in the hippocampus, and explore the possible molecular mechanism of cognitive impairment caused by SRS.
Method
1. SRS were induced by KA through intraperitoneal injection. Rats were randomly divided into control group, KA group and KA+VPA group. Next, according to the time point of behavioral tests, the above three groups were randomly divided into 2 w, 4w and 6w subgroups, respectively.
2. To evaluate cognitive function in every experiment subgroups by behavioral tests.
3. To evaluate pathology features of hippocampal neurons of KA and KA+VPA subgroups at 6w. Nissl staining by Toluidine Blue were performed.
4. Immunohistochemistry staining was used to detect expression of NR2B and PSD-95 proteins with time at different experiment subgroups by electron microscope.
5. RT-PCR analysis was used to detect alterations of NR2B and PSD-95 mRNA with time at different experiment subgroups.
6. Western blot analysis was used to detect alterations of NR2B and PSD-95 proteins with time at different experiment subgroups.
Result
1. Morris water maze, elevated-plus maze and open field analyses showed the cognitive impairment in three KA subgroups gradually became more serious with time (P<0.05), while there was no difference among KA-2w, control and KA+VPA subgroups at any time.
2. No extensive destruction was noted in the dentate gyrus, CA1 and CA3 subfields of hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of KA-6w subgroup rats.
3. Immunohistochemistry staining of NR2B and PSD-95 showed there were lots of trachychromatic brown NR2B and PSD-95 positive neurons in control group rats. Compared with NR2B and PSD-95 positive neurons in control group, those in KA-6w subgroup were fewer and shallower. But there was no significant difference between control subgroup and KA+VPA subgroup at any time.
4. RT-PCR analysis showed that expression of NR2B and PSD-95 mRNA in three KA subgroups were gradually down-regulated (P<0.05), while there was no difference among KA-2w, control and KA+VPA subgroups at any time.
5. Western blot analysis showed that expression of NR2B and PSD-95 protein in three KA subgroups were gradually down-regulated (P<0.05), while there was no difference among KA-2w, control and KA+VPA subgroups at any time.
Conclusion
1. SRS induced by KA may lead to cognitive impairment, which gradually become more serious with time.
2. At the present experiment, no extensive destruction was noted in hippocampus of rats post KA, areas of neuronal cell loss and gliosis were seen in hippocampus of KA-6w subgroup.
3. SRS induced by KA may decrease NR2B and PSD-95 expression, and consequently cause cognitive impairment.
4. VPA might improve cognitive impairment by maintain NR2B and PSD-95 expression.
Significance
Using a rodent TLE model induced by KA and evaluating behavioral deficits caused by SRS, we investigated and confirmed that synaptic plasticity-related proteins, such as NR2B, PSD-95, synaptophysin, SNAP-25, synaptotagmin 1 played an important role in cognitive impairment caused by SRS. Furthermore, we showed that VPA might improve cognitive impairment by maintain NR2B and PSD-95 expression. Studies on synaptic plasticity-related proteins will undoubtedly help us to know more about the possible mechamism of behavioral deficits caused by SRS. Thus, this study may provide new insights into therapeutic target and develop new neuroprotective drug improving cognitive impairment.
引文
1.Austin JK,Dunn DW.Progressive behavioral changes in children with epilepsy.Prog Brain Res 2002;135:419-427.
2.Huang L,Cilio MR,Silveira DC,et al.Long-term effects of neonatal seizures:a behavioral,electrophysiological,and histological study.Brain Res Dev Brain Res 1999;118(1-2):99-107.
3.Sayin U,Sutula TP,Stafstrom CE.Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety.Epilepsia 2004;45(12):1539-1548.
4.Gaitatzis A,Trimble MR,Sander JW.The psychiatric comorbidity of epilepsy.Acta Neurol Scand 2004;110(4):207-220.
5.Jokeit H,Ebner A.Long term effects of refractory temporal lobe epilepsy on cognitive abilities:a cross sectional study.J Neurol Neurosurg Psychiatry 1999;670):44-50.
6.Kwan P,Brodie MJ.Neuropsychological effects of epilepsy and antiepileptic drugs.Lancet 2001;357(9251):216-222.
7.Mula M,Trimble MR,Sander JW.The role of hippocampal sclerosis in topiramate-related depression and cognitive deficits in people with epilepsy.Epilepsia 2003;44(12):1573-1577.
8.Niikura Y,Abe K,Misawa M.Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats.Brain Res 2004;1017(1-2):218-221.
9. Dickson JM, Wilkinson ID, Howell SJ, Griffiths PD, Grunewald RA. Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy. J Neurol Neurosurg Psychiatry 2006; 77(7):834-840.
10. Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25(12):3667-3677.
11. Renaud J, Emond M, Meilleur S, Psarropoulou C, Carmant L. AIDA, a class I metabotropic glutamate-receptor antagonist limits kainate-induced hippocampal dysfunction. Epilepsia 2002; 43(11):1306-1317.
12. Lynch M, Sayin U, Golarai G, Sutula T. NMDA receptor-dependent plasticity of granule cell spiking in the dentate gyrus of normal and epileptic rats. J Neurophysiol 2000; 84(6):2868-2879.
13. Heynen AJ, Bear MR Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo. J Neurosci 2001; 21(24):9801-9813.
14. Li S, Anwyl R, Rowan MJ. A persistent reduction in short-term facilitation accompanies long-term potentiation in the CA1 area in the intact hippocampus. Neuroscience 2000; 100(2):213-220.
15. Hannesson DK, Wallace AE, Pollock M, Corley S, Mohapel P, Corcoran ME. The relation between extent of dorsal hippocampal kindling and delayed-match-to-place performance in the Morris water maze. Epilepsy Res 2004; 58(2-3): 145-154.
16. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401(6748):63-69.
17. Henshall DC, Chen J, Simon RP. Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. J Neurochem 2000; 74(3): 1215-1223.
18. Bragin A, Wilson CL, Engel J, Jr. Rate of interictal events and spontaneous seizures in epileptic rats after electrical stimulation of hippocampus and its afferents. Epilepsia 2002; 43 Suppl 5:81-85.
19. McMahon HT, Bolshakov VY, Janz R, Hammer RE, Siegelbaum SA, Sudhof TC. Synaptophysin, a major synaptic vesicle protein, is not essential for neurotransmitter release. Proc Natl Acad Sci U S A 1996; 93(10):4760-4764.
20. Janz R, Sudhof TC, Hammer RE, Unni V, Siegelbaum SA, Bolshakov VY. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 1999; 24(3):687-700.
21. Mullany PM, Lynch MA. Evidence for a role for synaptophysin in expression of long-term potentiation in rat dentate gyms. Neuroreport 1998; 9(11):2489-2494.
22. Mullany P, Lynch MA. Changes in protein synthesis and synthesis of the synaptic vesicle protein, synaptophysin, in entorhinal cortex following induction of long-term potentiation in dentate gyms: an age-related study in the rat. Neuropharmacology 1997; 36(7):973-980.
23. Chen YC, Chen QS, Lei JL, Wang SL. Physical training modifies the age-related decrease of GAP-43 and synaptophysin in the hippocampal formation in C57BL/6J mouse. Brain Res 1998; 806(2):238-245.
24. Selkoe DJ. Alzheimer's disease is a synaptic failure. Science 2002; 298(5594):789-791.
25. Suh EC, Jung YJ, Kim YA, Park EM, Lee KE. A beta 25-35 induces presynaptic changes in organotypic hippocampal slice cultures. Neurotoxicology 2008; 29(4):691-699.
26. Geddes JW, Hess EJ, Hart RA, Kesslak JP, Cotman CW, Wilson MC. Lesions of hippocampal circuitry define synaptosomal-associated protein-25 (SNAP-25) as a novel presynaptic marker. Neuroscience 1990; 38(2):515-525.
27. Oyler GA, Polli JW, Higgins GA, Wilson MC, Billingsley ML. Distribution and expression of SNAP-25 immunoreactivity in rat brain, rat PC-12 cells and human SMS-KCNR neuroblastoma cells. Brain Res Dev Brain Res 1992; 65(2):133-146.
28. Mehta PP, Battenberg E, Wilson MC. SNAP-25 and synaptotagmin involvement in the final Ca(2+)-dependent triggering of neurotransmitter exocytosis. Proc Natl Acad Sci U S A 1996; 93(19): 10471-10476.
29. Banerjee A, Kowalchyk JA, DasGupta BR, Martin TF. SNAP-25 is required for a late postdocking step in Ca2+-dependent exocytosis. J Biol Chem 1996; 271(34):20227-20230.
30. Jahn R, Lang T, Sudhof TC. Membrane fusion. Cell 2003; 112(4):519-533.
31. Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci 2004; 27:509-547.
32. Roberts LA, Morris BJ, O'Shaughnessy CT. Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus. Neuroreport 1998; 9(1):33-36.
33. Hou Q, Gao X, Zhang X, et al. SNAP-25 in hippocampal CA1 region is involved in memory consolidation. Eur J Neurosci 2004; 20(6): 1593-1603.
34. Hou QL, Gao X, Lu Q, et al. SNAP-25 in hippocampal CA3 region is required for long-term memory formation. Biochem Biophys Res Commun 2006; 347(4):955-962.
35. Gosso MF, de Geus EJ, van Belzen MJ, et al. The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts. Mol Psychiatry 2006; 11(9):878-886.
36. Spellmann I, Muller N, Musil R, et al. Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci 2008; 258(6):335-344.
37. Fukuda M. Molecular cloning and characterization of human, rat, and mouse synaptotagmin XV. Biochem Biophys Res Commun 2003; 306(1):64-71.
38. Fernandez-Chacon R, Konigstorfer A, Gerber SH, et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 2001; 410(6824):41-49.
39. Sudhof TC. Synaptotagmins: why so many? J Biol Chem 2002; 277(10):7629-7632.
40. Koh TW, Bellen HJ. Synaptotagmin I, a Ca2+ sensor for neurotransmitter release. Trends Neurosci 2003; 26(8):413-422.
41. Chen GH, Wang YJ, Qin S, Yang QG, Zhou JN, Liu RY. Age-related spatial cognitive impairment is correlated with increase of synaptotagmin 1 in dorsal hippocampus in SAMP8 mice. Neurobiol Aging 2007; 28(4):611-618.
42. Reddy PH, Mani G, Park BS, et al. Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alzheimers Dis 2005; 7(2):103-117; discussion 173-180.
43. Hanaya R, Boehm N, Nehlig A. Dissociation of the immunoreactivity of synaptophysin and GAP-43 during the acute and latent phases of the lithium-pilocarpine model in the immature and adult rat. Exp Neurol 2007; 204(2):720-732.
44. Zhang Y, Vilaythong AP, Yoshor D, Noebels JL. Elevated thalamic low-voltage-activated currents precede the onset of absence epilepsy in the SNAP25-deficient mouse mutant coloboma. J Neurosci 2004; 24(22):5239-5248.
45. Xiao Z, Gong Y, Wang XF, et al. Altered Expression of Synaptotagmin I In Temporal Lobe Tissue of Patients With Refractory Epilepsy. J Mol Neurosci 2008.
46. Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol 1972; 32(3):295-299.
47. Adams SV, Winterer J, Muller W. Muscarinic signaling is required for spike-pairing induction of long-term potentiation at rat Schaffer collateral-CA1 synapses. Hippocampus 2004; 14(4):413-416.
48. Lee JI, Ahnn J. Calcineurin in animal behavior. Mol Cells 2004; 17(3):390-396.
49. Blank T, Nijholt I, Kye MJ, Spiess J. Small conductance Ca2+-activated K+ channels as targets of CNS drug development. Curr Drug Targets CNS Neurol Disord 2004;3(3):161-167.
50. Tseng KY, O'Donnell P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 2004; 24(22):5131-5139.
51. Moyano S, Frechilla D, Del Rio J. NMDA receptor subunit and CaMKII changes in rat hippocampus induced by acute MDMA treatment: a mechanism for learning impairment. Psychopharmacology (Berl) 2004; 173(3-4):337-345.
52. Beck H, Goussakov IV, Lie A, Helmstaedter C, Elger CE. Synaptic plasticity in the human dentate gyrus. J Neurosci 2000; 20(18):7080-7086.
53. Okada T, Yamada N, Tsuzuki K, Horikawa HP, Tanaka K, Ozawa S. Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning. Eur J Neurosci 2003; 17(2):341-349.
54. Stanton PK, Gage AT. Distinct synaptic loci of Ca2+/calmodulin-dependent protein kinase II necessary for long-term potentiation and depression. J Neurophysiol 1996; 76(3):2097-2101.
55. Hannesson DK, Mohapel P, Corcoran ME. Dorsal hippocampal kindling selectively impairs spatial learning/short-term memory. Hippocampus 2001; ll(3):275-286.
56. Leung LS, Wu C. Kindling suppresses primed-burst-induced long-term potentiation in hippocampal CA1. Neuroreport 2003; 14(2):211-214.
57. Sudhof TC, Lottspeich F, Greengard P, Mehl E, Jahn R. The cDNA and derived amino acid sequences for rat and human synaptophysin. Nucleic Acids Res 1987; 15(22):9607.
58. Pang DT, Wang JK, Valtorta F, Benfenati F, Greengard P. Protein tyrosine phosphorylation in synaptic vesicles. Proc Natl Acad Sci U S A 1988; 85(3):762-766.
59. Rubenstein JL, Greengard P, Czernik AJ. Calcium-dependent serine phosphorylation of synaptophysin. Synapse 1993; 13(2): 161-172.
60. Shaw GM, Wasserman CR, Lammer EJ, et al. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 1996; 58(3):551-561.
61. Wiedenmann B, Franke WW. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 1985; 41(3):1017-1028.
62. Daly C, Sugimori M, Moreira JE, Ziff EB, Llinas R. Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles. Proc Natl Acad Sci U S A 2000;97(11):6120-6125.
63. Daly C, Ziff EB. Ca2+-dependent formation of a dynamin-synaptophysin complex: potential role in synaptic vesicle endocytosis. J Biol Chem 2002; 277(11):9010-9015.
64. Tarsa L, Goda Y. Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 2002; 99(2):1012-1016.
65. Looney MR, Dohan FC, Jr., Davies KG, Seidenberg M, Hermann BP, Schweitzer JB. Synaptophysin immunoreactivity in temporal lobe epilepsy-associated hippocampal sclerosis. Acta Neuropathol 1999; 98(2):179-185.
66. Heffeman JM, Eastwood SL, Nagy Z, Sanders MW, McDonald B, Harrison PJ. Temporal cortex synaptophysin mRNA is reduced in Alzheimer's disease and is negatively correlated with the severity of dementia. Exp Neurol 1998; 150(2):235-239.
67. Callahan LM, Vaules WA, Coleman PD. Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol 1999; 58(3):275-287.
68. Landen M, Davidsson P, Gottfries CG, Grenfeldt B, Stridsberg M, Blennow K. Reduction of the small synaptic vesicle protein synaptophysin but not the large dense core chromogranins in the left thalamus of subjects with schizophrenia. Biol Psychiatry 1999; 46(12):1698-1702.
69. Eastwood SL, Harrison PJ. Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections. Neuroscience 1999; 93(1):99-106.
70. Karson CN, Mrak RE, Schluterman KO, Sturner WQ, Sheng JG, Griffin WS. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'. Mol Psychiatry 1999; 4(1):39-45.
71. Glantz LA, Austin MC, Lewis DA. Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 2000; 48(5):389-397.
72. Sollner T, Whiteheart SW, Brunner M, et al. SNAP receptors implicated in vesicle targeting and fusion. Nature 1993; 362(6418):318-324.
73. Low P, Norlin T, Risinger C, et al. Inhibition of neurotransmitter release in the lamprey reticulospinal synapse by antibody-mediated disruption of SNAP-25 function. Eur J Cell Biol 1999; 78(11):787-793.
74. Duc C, Catsicas S. Ultrastructural localization of SNAP-25 within the rat spinal cord and peripheral nervous system. J Comp Neurol 1995; 356(1):152-163.
75. Grosse G, Grosse J, Tapp R, et al. SNAP-25 requirement for dendritic growth of hippocampal neurons. J Neurosci Res 1999; 56(5):539-546.
76. Lan JY, Skeberdis VA, Jover T, Zheng X, Bennett MV, Zukin RS. Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking. J Neurosci 2001; 21(16):6058-6068.
77. Osen-Sand A, Catsicas M, Staple JK, et al. Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature 1993; 364(6436):445-448.
78. Shirasu M, Kimura K, Kataoka M, et al. VAMP-2 promotes neurite elongation and SNAP-25A increases neurite sprouting in PC12 cells. Neurosci Res 2000; 37(4):265-275.
79. Braun JE, Madison DV. A novel SNAP25-caveolin complex correlates with the onset of persistent synaptic potentiation. J Neurosci 2000; 20(16):5997-6006.
80. Steffensen SC, Wilson MC, Henriksen SJ. Coloboma contiguous gene deletion encompassing Snap alters hippocampal plasticity. Synapse 1996; 22(3):281-289.
81. Tucker WC, Chapman ER. Role of synaptotagmin in Ca2+-triggered exocytosis. Biochem J 2002; 366(Pt 1):1-13.
82. Weimer RM, Jorgensen EM. Controversies in synaptic vesicle exocytosis. J Cell Sci 2003; 116(Pt 18):3661-3666.
83. Li L, Chin LS. The molecular machinery of synaptic vesicle exocytosis. Cell Mol Life Sci 2003; 60(5):942-960.
84. Stevens CF, Sullivan JM. The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission. Neuron 2003; 39(2):299-308.
85. Wang CT, Lu JC, Bai J, et al. Different domains of synaptotagmin control the choice between kiss-and-run and full fusion. Nature 2003; 424(6951):943-947.
86. Littleton JT, Bai J, Vyas B, et al. synaptotagmin mutants reveal essential functions for the C2B domain in Ca2+-triggered fusion and recycling of synaptic vesicles in vivo. J Neurosci 2001; 21(5): 1421-1433.
87. Nicholson-Tomishima K, Ryan TA. Kinetic efficiency of endocytosis at mammalian CNS synapses requires synaptotagmin I. Proc Natl Acad Sci U S A2004; 101(47):16648-16652.
88. Poskanzer KE, Marek KW, Sweeney ST, Davis GW. Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo. Nature 2003; 426(6966):559-563.
89. Rickman C, Davletov B. Mechanism of calcium-independent synaptotagmin binding to target SNAREs. J Biol Chem 2003; 278(8):5501-5504.
90. Bai J, Chapman ER. The C2 domains of synaptotagmin--partners in exocytosis. Trends Biochem Sci 2004; 29(3): 143-151.
91. Masliah E, Mallory M, Alford M, et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology 2001; 56(1):127-129.
92. Sze CI, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ. Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains. J Neurol Sci 2000; 175(2):81-90.
93. Takamori M. Lambert-Eaton myasthenic syndrome as an autoimmune calcium channelopathy. Biochem Biophys Res Commun 2004; 322(4):1347-1351.
94. Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51(1):41-48.
95. Yin S, Guan Z, Tang Y, Zhao J, Hong J, Zhang W. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005; 1053(1-2):195-202.
96. Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67(8): 1383-1389.
97. Lee CL, Hannay J, Hrachovy R, Rashid S, Antalffy B, Swann JW. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 2001; 107(1):71-84.
98. Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 2003; 54(6):706-718.
99. Su SW, Cilio MR, Sogawa Y, Silveira DC, Holmes GL, Stafstrom CE. Timing of ketogenic diet initiation in an experimental epilepsy model. Brain Res Dev Brain Res 2000; 125(1-2):131-138.
100. Haas KZ, Sperber EF, Opanashuk LA, Stanton PK, Moshe SL. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus 2001; 11(6):615-625.
101. Chen LS, Wong JG, Banerjee PK, Snead OC, 3rd. Kainic acid-induced focal cortical seizure is associated with an increase of synaptophysin immunoreactivity in the cortex. Exp Neurol 1996; 141(1):25-31.
102. Costantin L, Bozzi Y, Richichi C, et al. Antiepileptic effects of botulinum neurotoxin E.J Neurosci 2005;25(8):1943-1951.
103.Yang JW,Czech T,Felizardo M,Baumgartner C,Lubec G.Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy.Amino Acids 2006;30(4):477-493.
104.Frankland PW,Bontempi B.The organization of recent and remote memories.Nat Rev Neurosci 2005;6(2):119-130.
1. Austin JK, Dunn DW. Progressive behavioral changes in children with epilepsy. Prog Brain Res 2002; 135:419-427.
2. Huang L, Cilio MR, Silveira DC, et al. Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Brain Res Dev Brain Res 1999;118(1-2):99-107.
3. Sayin U, Sutula TP, Stafstrom CE. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 2004; 45(12):1539-1548.
4. Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004; 110(4):207-220.
5. Jokeit H, Ebner A. Long term effects of refractory temporal lobe epilepsy on cognitive abilities: a cross sectional study. J Neurol Neurosurg Psychiatry 1999; 67(1):44-50.
6. Niikura Y, Abe K, Misawa M. Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats. Brain Res 2004; 1017(1-2):218-221.
7. Renaud J, Emond M, Meilleur S, Psarropoulou C, Carmant L. AIDA, a class I metabotropic glutamate-receptor antagonist limits kainate-induced hippocampal dysfunction. Epilepsia 2002; 43(11):1306-1317.
8. Teyler TJ, DiScenna P. Long-term potentiation. Annu Rev Neurosci 1987; 10:131-161.
9. Yamakura T, Shimoji K. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog Neurobiol 1999; 59(3):279-298.
10. Esplugues JV. NO as a signalling molecule in the nervous system. Br J Pharmacol 2002; 135(5): 1079-1095.
11. Katzoff A, Ben-Gedalya T, Susswein AJ. Nitric oxide is necessary for multiple memory processes after learning that a food is inedible in aplysia. J Neurosci 2002; 22(21):9581-9594.
12. Meyer RC, Spangler EL, Kametani H, Ingram DK. Age-associated memory impairment. Assessing the role of nitric oxide. Ann N Y Acad Sci 1998; 854:307-317.
13. Paul V, Reddy L, Ekambaram P. Prevention of picrotoxin convulsions-induced learning and memory impairment by nitric oxide increasing dose of L-arginine in rats. Pharmacol Biochem Behav 2003; 75(2):329-334.
14. Wu J, Huang KP, Huang FL. Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+- and Ca2+/calmodulin-dependent neuronal signaling in the hippocampus. J Neurochem 2003; 86(6): 1524-1533.
15. Mishina M, Mori H, Araki K, et al. Molecular and functional diversity of the NMDA receptor channel. Ann N Y Acad Sci 1993; 707:136-152.
16. Sakimura K, Kutsuwada T, Ito I, et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 1995; 373(6510):151-155.
17. Kiyama Y, Manabe T, Sakimura K, Kawakami F, Mori H, Mishina M. Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilonl subunit. J Neurosci 1998; 18(17):6704-6712.
18. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401(6748):63-69.
19. Kennedy MB. Signal-processing machines at the postsynaptic density. Science 2000; 290(5492):750-754.
20. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 1995; 269(5231):1737-1740.
21. Nusser Z, Mulvihill E, Streit P, Somogyi P. Subsynaptic segregation of metabotropic and ionotropic glutamate receptors as revealed by immunogold localization. Neuroscience 1994; 61(3):421-427.
22. Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998; 396(6710):433-439.
23. Brandt C, Gastens AM, Sun M, Hausknecht M, Loscher W. Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology 2006; 51(4):789-804.
24. Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy. J Neurosci 2002; 22(14):6052-6061.
25. Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol 1972; 32(3):295-299.
26. Duprat F, Daw M, Lim W, Collingridge G, Isaac J. GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 2003; 358(1432):715-720.
27. Watt AJ, Sjostrom PJ, Hausser M, Nelson SB, Turrigiano GG.A proportional but slower NMDA potentiation follows AMPA potentiation in LTP. Nat Neurosci 2004; 7(5):518-524.
28. Taverna FA, Georgiou J, McDonald RJ, et al. Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation. J Physiol 2005; 565(Pt 2):579-591.
29. Erreger K, Dravid SM, Banke TG, Wyllie DJ, Traynelis SF. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J Physiol 2005; 563(Pt 2):345-358.
30. Woodside BL, Borroni AM, Hammonds MD, Teyler TJ. NMDA receptors and voltage-dependent calcium channels mediate different aspects of acquisition and retention of a spatial memory task. Neurobiol Learn Mem 2004; 81(2):105-114.
31. Clayton DA, Mesches MH, Alvarez E, Bickford PC, Browning MD. A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 2002; 22(9):3628-3637.
32. O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES. AMPA receptor potentiators for the treatment of CNS disorders. Curr Drug Targets CNS Neurol Disord 2004; 3(3):181-194.
33. Sessoms-Sikes S, Honse Y, Lovinger DM, Colbran RJ. CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism. Mol Cell Neurosci 2005; 29(1):139-147.
34. Rosenblum K, Futter M, Voss K, et al. The role of extracellular regulated kinases I/II in late-phase long-term potentiation. J Neurosci 2002; 22(13):5432-5441.
35. Poommipanit PB, Chen B, Oltvai ZN. Interleukin-3 induces the phosphorylation of a distinct fraction of bcl-2. J Biol Chem 1999; 274(2): 1033-1039.
36. Lonart G.RIM1: an edge for presynaptic plasticity. Trends Neurosci 2002; 25(7):329-332.
37. Lennmyr F, Karlsson S, Gerwins P, Ata KA, Terent A. Activation of mitogen-activated protein kinases in experimental cerebral ischemia. Acta Neurol Scand 2002; 106(6):333-340.
38. Chien WL, Liang KC, Teng CM, Kuo SC, Lee FY, Fu WM. Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1. Eur J Neurosci 2005; 21 (6): 1679-1688.
39. Yuan LL, Adams JP, Swank M, Sweatt JD, Johnston D. Protein kinase modulation of dendritic K+ channels in hippocampus involves a mitogen-activated protein kinase pathway. J Neurosci 2002; 22(12):4860-4868.
40. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361(6407):31-39.
41. Behe P, Stern P, Wyllie DJ, Nassar M, Schoepfer R, Colquhoun D. Determination of NMDA NR1 subunit copy number in recombinant NMDA receptors. Proc Biol Sci 1995; 262(1364):205-213.
42. Premkumar LS, Auerbach A. Stoichiometry of recombinant N-methyl-D-aspartate receptor channels inferred from single-channel current patterns. J Gen Physiol 1997; 110(5):485-502.
43. Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA. Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 1995; 15(10):6498-6508.
44. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51(1):7-61.
45. Lieberman DN, Mody I. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 1994; 369(6477):235-239.
46. Omkumar RV, Kiely MJ, Rosenstein AJ, Min KT, Kennedy MB. Identification of a phosphorylation site for calcium/calmodulindependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 1996; 271(49):31670-31678.
47. Kuner T, Wollmuth LP, Karlin A, Seeburg PH, Sakmann B. Structure of the NMDA receptor channel M2 segment inferred from the accessibility of substituted cysteines. Neuron 1996; 17(2):343-352.
48. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994; 12(3):529-540.
49. Kutsuwada T, Sakimura K, Manabe T, et al. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 1996; 16(2):333-344.
50. Thompson CL, Drewery DL, Atkins HD, Stephenson FA, Chazot PL. Immunohistochemical localization of N-methyl-D-aspartate receptor NR1, NR2A, NR2B and NR2C/D subunits in the adult mammalian cerebellum. Neurosci Lett 2000; 283(2):85-88.
51. Charton JP, Herkert M, Becker CM, Schroder H. Cellular and subcellular localization of the 2B-subunit of the NMDA receptor in the adult rat telencephalon. Brain Res 1999; 816(2):609-617.
52. Momiyama A. Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord. J Physiol 2000; 523 Pt 3:621-628.
53. Scheetz AJ, Constantine-Paton M. Modulation of NMDA receptor function: implications for vertebrate neural development. Faseb J 1994; 8(10):745-752.
54. Tovar KR, Westbrook GL. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 1999; 19(10):4180-4188.
55. Sasner M, Buonanno A. Distinct N-methyl-D-aspartate receptor 2B subunit gene sequences confer neural and developmental specific expression. J Biol Chem 1996; 271(35):21316-21322.
56. Klein M, Pieri I, Uhlmann F, Pfizenmaier K, Eisel U. Cloning and characterization of promoter and 5'-UTR of the NMDA receptor subunit epsilon 2: evidence for alternative splicing of 5'-non-coding exon. Gene 1998; 208(2):259-269.
57. Matus A. Actin-based plasticity in dendritic spines. Science 2000; 290(5492):754-758.
58. Okabe S, Miwa A, Okado H. Spine formation and correlated assembly of presynaptic and postsynaptic molecules. J Neurosci 2001; 21(16):6105-6114.
59. Lendvai B, Stern EA, Chen B, Svoboda K. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Nature 2000; 404(6780):876-881.
60. Ziv NE, Garner CC. Principles of glutamatergic synapse formation: seeing the forest for the trees. Curr Opin Neurobiol 2001; 11(5):536-543.
61. Baker KB, Kim JJ. Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats. Learn Mem 2002; 9(2):58-65.
62. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS. PSD-95 involvement in maturation of excitatory synapses. Science 2000; 290(5495): 1364-1368.
63. Roche KW, Standley S, McCallum J, Dune Ly C, Ehlers MD, Wenthold RJ. Molecular determinants of NMDA receptor internalization. Nat Neurosci 2001; 4(8):794-802.
64. Carroll RC, Beattie EC, von Zastrow M, Malenka RC. Role of AMPA receptor endocytosis in synaptic plasticity. Nat Rev Neurosci 2001; 2(5):315-324.
65. Steigerwald F, Schulz TW, Schenker LT, Kennedy MB, Seeburg PH, Kohr G. C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors. J Neurosci 2000; 20(12):4573-4581.
66. Barria A, Malinow R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 2002; 35(2):345-353.
67. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002; 5(5):405-414.
68. Fong DK, Rao A, Crump FT, Craig AM. Rapid synaptic remodelmg by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II. J Neurosci 2002; 22(6):2153-2164.
69. Clayton DA, Browning MD. Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats. Neurobiol Aging 2001; 22(1):165-168.
70. Shimizu E, Tang YP, Rampon C, Tsien JZ. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 2000; 290(5494): 1170-1174.
71. Turchi J, Sarter M. Antisense oligodeoxynucleotide-induced suppression of basal forebrain NMDA-NR1 subunits selectively impairs visual attentional performance in rats. Eur J Neurosci 2001; 14(1):103-117.
72. Ito I, Kawakami R, Sakimura K, Mishina M, Sugiyama H. Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses. Neuropharmacology 2000; 39(6):943-951.
73. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T. Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor epsilonl subunit. J Neurosci 2001; 21(2):750-757.
74. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T. Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor epsilon 4 subunit. J Neurosci 2002; 22(6):2335-2342.
75. Lee I, Kesner RP. Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory. Nat Neurosci 2002; 5(2):162-168.
76. Sheng M. The postsynaptic NMDA-receptor--PSD-95 signaling complex in excitatory synapses of the brain. J Cell Sci 2001; 114(Pt 7):1251.
77. Lin Y, Skeberdis VA, Francesconi A, Bennett MV, Zukin RS. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 2004; 24(45):10138-10148.
78. Dong YN, Waxman EA, Lynch DR. Interactions of postsynaptic density-95 and the NMDA receptor 2 subunit control calpain-mediated cleavage of the NMDA receptor. J Neurosci 2004; 24(49):11035-11045.
79. Losi G, Prybylowski K, Fu Z, Luo J, Wenthold RJ, Vicini S. PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat. J Physiol 2003; 548(Pt l):21-29.
80. Li B, Otsu Y, Murphy TH, Raymond LA. Developmental decrease in NMDA receptor desensitization associated with shift to synapse and interaction with postsynaptic density-95. J Neurosci 2003; 23(35): 11244-11254.
81. Colledge M, Dean RA, Scott GK, Langeberg LK, Huganir RL, Scott JD. Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 2000;27(1):107-119.
82. Yan XB, Song B, Zhang GY. Postsynaptic density protein 95 mediates Ca2+/calmodulin-dependent protein kinase II-activated serine phosphorylation of neuronal nitric oxide synthase during brain ischemia in rat hippocampus. Neurosci Lett 2004; 355(3): 197-200.
83. Christopherson KS, Hillier BJ, Lim WA, Bredt DS. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 1999; 274(39):27467-27473.
84. Brenman JE, Chao DS, Gee SH, et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alphal-syntrophin mediated by PDZ domains. Cell 1996; 84(5):757-767.
85. Ishii H, Shibuya K, Ohta Y, et al. Enhancement of nitric oxide production by association of nitric oxide synthase with N-methyl-D-aspartate receptors via postsynaptic density 95 in genetically engineered Chinese hamster ovary cells: real-time fluorescence imaging using nitric oxide sensitive dye. J Neurochem 2006; 96(6): 1531-1539.
86. Stein V, House DR, Bredt DS, Nicoll RA. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression. J Neurosci 2003; 23(13):5503-5506.
87. Wyneken U, Marengo JJ, Villanueva S, et al. Epilepsy-induced changes in signaling systems of human and rat postsynaptic densities. Epilepsia 2003; 44(2):243-246.
88. Wyneken U, Smalla KH, Marengo JJ, et al. Kainate-induced seizures alter protein composition and N-methyl-D-aspartate receptor function of rat forebrain postsynaptic densities. Neuroscience 2001; 102(1):65-74.
89. Nakazawa T, Tezuka T, Yamamoto T. [Regulation of NMDA receptor function by Fyn-mediated tyrosine phosphorylation]. Nihon Shinkei Seishin Yakurigaku Zasshi 2002; 22(5): 165-167.
90. Colledge M, Snyder EM, Crozier RA, et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 2003; 40(3):595-607.
91. Aarts M, Liu Y, Liu L, et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 2002; 298(5594):846-850.
92. Savinainen A, Garcia EP, Dorow D, Marshall J, Liu YF. Kainate receptor activation induces mixed lineage kinase-mediated cellular signaling cascades via post-synaptic density protein 95.J Biol Chem 2001;276(14):11382-11386.
93.Pei DS,Wang XT,Liu Y,et al.Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence.Brain 2006;129(Pt 2):465-479.
94.Hou XY,Zhang GY,Wang DG,Guan QH,Yan JZ.Suppression of postsynaptic density protein 95 by antisense oligonucleotides diminishes postischemic pyramidal cell death in rat hippocampal CA1 subfield.Neurosci Lett 2005;385(3):230-233.
95.Pei DS,Sun YF,Guan QH,Hao ZB,Xu TL,Zhang GY.Postsynaptic density protein 95 antisense oligodeoxynucleotides inhibits the activation of MLK3and JNK3 via the GluR6.PSD-95.MLK3 signaling module after transient cerebral ischemia in rat hippocampus.Neurosci Lett 2004;367(1):71-75.
96.Gylys KH,Fein JA,Yang F,Wiley DJ,Miller CA,Cole GM.Synaptic changes in Alzheimer's disease:increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence.Am J Pathol 2004;165(5):1809-1817.
97.Kelly BL,Ferreira A.beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons.J Biol Chem 2006;281(38):28079-28089.
98.Yao M,Nguyen TV,Pike CJ.Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w.J Neurosci 2005;25(5):1149-1158.
99.Morishima Y,Gotoh Y,Zieg J,et al.Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand.J Neurosci 2001;21(19):7551-7560.
100.Lee ST,Kim M.Aging and neurodegeneration.Molecular mechanisms of neuronal loss in Huntington's disease.Mech Ageing Dev 2006;127(5):432-435.
101.Kajimoto Y,Shirakawa O,Lin XH,et al.Synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP) is expressed differentially in phencyclidine-treated rats and is increased in the nucleus accumbens of patients with schizophrenia. Neuropsychopharmacology 2003; 28(10):1831-1839.
102. Bao J, Lin H, Ouyang Y, et al. Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nat Neurosci 2004; 7(11):1250-1258.
103. Hahn CG, Wang HY, Cho DS, et al. Altered neuregulin l-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006; 12(7):824-828.
104. Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51(1):41-48.
105. Yin S, Guan Z, Tang Y, Zhao J, Hong J, Zhang W. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005; 1053(1-2):195-202.
106. Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67(8):1383-1389.
107. Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25(12):3667-3677.
108. Lee CL, Hannay J, Hrachovy R, Rashid S, Antalffy B, Swann JW. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 2001; 107(1):71-84.
109. Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 2003; 54(6):706-718.
110. Su SW, Cilio MR, Sogawa Y, Silveira DC, Holmes GL, Stafstrom CE. Timing of ketogenic diet initiation in an experimental epilepsy model. Brain Res Dev Brain Res 2000;125(1-2):131-138.
111.Haas KZ,Sperber EF,Opanashuk LA,Stanton PK,Moshe SL.Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling.Hippocampus 2001;11(6):615-625.
112.Frankland PW,Bontempi B.The organization of recent and remote memories.Nat Rev Neurosci 2005;6(2):119-130.
[1] Stables JP, Bertram EH, White HS, et al. Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia 2002; 43:1410-1420.
[2] Austin JK, Dunn DW. Progressive behavioral changes in children with epilepsy. Prog Brain Res 2002; 135:419-427.
[3] Huang L, Cilio MR, Silveira DC, et al. Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Brain Res Dev Brain Res 1999; 118:99-107.
[4] Sayin U, Sutula TP, Stafstrom CE. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 2004; 45:1539-1548.
[5] Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004; 110:207-220.
[6] Jokeit H, Ebner A. Long term effects of refractory temporal lobe epilepsy on cognitive abilities: a cross sectional study. J Neurol Neurosurg Psychiatry 1999; 67:44-50.
[7] Loscher W. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res 2002; 50:105-123.
[8] Nadler JV. Minireview. Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 1981; 29:2031-2042.
[9] Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51:41-48.
[10]Becker A, Letzel K, Letzel U, Grecksch G. Kindling of the dorsal and the ventral hippocampus: effects on learning performance in rats. Physiol Behav 1997; 62:1265-1271.
[11]Haut SR, Veliskova J, Moshe SL. Susceptibility of immature and adult brains to seizure effects. Lancet Neurol 2004; 3:608-617.
[12]Sutula T, Lauersdorf S, Lynch M, Jurgella C, Woodard A. Deficits in radial arm maze performance in kindled rats: evidence for long-lasting memory dysfunction induced by repeated brief seizures. JNeurosci 1995; 15:8295-8301.
[13]Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 1999; 399:66-70.
[14]Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25:3667-3677.
[15]Calabresi P, Saulle E, Centonze D, Pisani A, Marfia GA, Bernardi G. Post-ischaemic long-term synaptic potentiation in the striatum: a putative mechanism for cell type-specific vulnerability. Brain 2002; 125:844-860.
[16]McBain CJ, Mayer ML. N-methyl-D-aspartic acid receptor structure and function. Physiol Rev 1994; 74:723-760.
[17]Loftis JM, Janowsky A. The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther 2003; 97:55-85.
[18]Riedel G. Function of metabotropic glutamate receptors in learning and memory. Trends Neurosci 1996; 19:219-224.
[19]Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH. Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 1997; 51:23-32.
[20]Gardoni F, Schrama LH, Kamal A, Gispen WH, Cattabeni F, Di Luca M. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor. J Neurosci 2001; 21:1501 -1509.
[21]Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998; 396:433-439.
[22]Pollak DD, Herkner K, Hoeger H, Lubec G. Behavioral testing upregulates pCaMKII, BDNF, PSD-95 and egr-1 in hippocampus of FVB/N mice. Behav Brain Res 2005; 163:128-135.
[23]Nyffeler M, Zhang WN, Feldon J, Knuesel I. Differential expression of PSD proteins in age-related spatial learning impairments. Neurobiol Aging 2007; 28:143-155.
[24]Waxman EA, Lynch DR. N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist 2005; 11:37-49.
[25]Kennedy MB. Signal-processing machines at the postsynaptic density. Science 2000; 290:750-754.
[26]Williams JM, Guevremont D, Kennard JT, Mason-Parker SE, Tate WP, Abraham WC. Long-term regulation of N-methyl-D-aspartate receptor subunits and associated synaptic proteins following hippocampal synaptic plasticity. Neuroscience 2003; 118:1003-1013.
[27]Jiang Q, Wang J, Wu X, Jiang Y. Alterations of NR2B and PSD-95 expression after early-life epileptiform discharges in developing neurons. Int J Dev Neurosci 2007; 25:165-170.
[28]Brandt C, Gastens AM, Sun M, Hausknecht M, Loscher W. Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology 2006; 51:789-804.
[29]Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy. J Neurosci 2002; 22:6052-6061.
[30]Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol 1972; 32:295-299.
[31]Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 2003; 463:3-33.
[32]Liu FY, Wang XF, Li MW, et al. Upregulated expression of postsynaptic density-93 and N-methyl-D-aspartate receptors subunits 2B mRNA in temporal lobe tissue of epilepsy. Biochem Biophys Res Commun 2007; 358:825-830.
[33] Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11:47-60.
[34] Yin S, Guan Z, Tang Y, Zhao J, Hong J, Zhang W. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005; 1053:195-202.
[35]Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67:1383-1389.
[36] Lee CL, Hannay J, Hrachovy R, Rashid S, Antalffy B, Swann JW. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 2001; 107:71-84.
[37]Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 2003; 54:706-718.
[38]Haas KZ, Sperber EF, Opanashuk LA, Stanton PK, Moshe SL. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus 2001; 11:615-625.
[39]Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci 2005; 6:119-130.
[40]Gultekin F, Karakoyun I, Sutcu R, et al. Chlorpyrifos increases the levels of hippocampal NMDA receptor subunits NR2A and NR2B in juvenile and adult rats. Int J Neurosci 2007; 117:47-62.
[41]Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401:63-69.
[42]Wong RW, Setou M, Teng J, Takei Y, Hirokawa N. Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc Natl Acad Sci U S A 2002; 99:14500-14505.
[43]Cao X, Cui Z, Feng R, et al. Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur J Neurosci 2007; 25:1815-1822.
[44] Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci 2004; 5:771-781.
[45]Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A 2007; 104:13501-13506.
Austin, J. K. and Dunn, D. W., 2002. Progressive behavioral changes in children with epilepsy. Prog Brain Res. 135,419-427.
Bannerman, D. M., Deacon, R.M., Offen, S., Friswell, J., Grubb, M. and Rawlins, J. N., 2002. Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behav Neurosci. 116, 884-901.
Bennett, J. C., McRae, P. A., Levy, L. J. and Frick, K. M., 2006. Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice. Neurobiol Learn Mem. 85,139-152.
Bliss, T. V. and Collingridge, G. L., 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 361, 31-39.
Bolanos, A. R., Sarkisian, M., Yang, Y., Hori, A., Helmers, S. L., Mikati, M., Tandon, P., Stafstrom, C. E. and Holmes, G. L., 1998. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology. 51,41-48.
Calabrese, B., Shaked, G. M., Tabarean, I. V., Braga, J., Koo, E. H. and Halpain, S., 2007. Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Mol Cell Neurosci. 35,183-193.
Calhoun, M. E., Kurth, D., Phinney, A. L., Long, J. M., Hengemihle, J., Mouton, P. R., Ingram, D. K. and Jucker, M., 1998. Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice. Neurobiol Aging. 19, 599-606.
Chang, Y. C., Huang, A. M., Kuo, Y. M., Wang, S. T., Chang, Y. Y. and Huang, C. C., 2003. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol. 54, 706-718.
Chen, G. H., Wang, Y. J., Qin, S., Yang, Q. G., Zhou, J. N. and Liu, R. Y, 2007. Age-related spatial cognitive impairment is correlated with increase of synaptotagmin 1 in dorsal hippocampus in SAMP8 mice. Neurobiol Aging. 28, 611-618.
Chen, L. S., Wong, J. G., Banerjee, P. K. and Snead, O. C., 3rd, 1996. Kainic acid-induced focal cortical seizure is associated with an increase of synaptophysin immunoreactivity in the cortex. Exp Neurol. 141,25-31.
Cheung, M. C., Chan, A. S., Chan, Y. L., Lam, J. M. and Lam, W., 2006. Effects of illness duration on memory processing of patients with temporal lobe epilepsy. Epilepsia. 47,1320-1328.
Costantin, L., Bozzi, Y., Richichi, C., Viegi, A., Antonucci, F., Funicello, M., Gobbi, M., Mennini, T., Rossetto, O., Montecucco, C., Maffei, L., Vezzani, A. and Caleo, M., 2005. Antiepileptic effects of botulinum neurotoxin E. J Neurosci. 25,1943-1951.
Dickson, J.M., Wilkinson, I. D., Howell, S. J., Griffiths, P. D. and Grunewald, R. A., 2006. Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy. J Neurol Neurosurg Psychiatry. 77, 834-840.
Engert, F. and Bonhoeffer, T., 1999. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 399, 66-70.
Fernandez-Chacon, R., Konigstorfer, A., Gerber, S. H., Garcia, J., Matos, M. F., Stevens, C. F., Brose, N., Rizo, J., Rosenmund, C. and Sudhof, T. C., 2001. Synaptotagmin I functions as a calcium regulator of release probability. Nature. 410,41-49.
File, S. E., 1993. The interplay of learning and anxiety in the elevated plus-maze. Behav Brain Res. 58,199-202.
Frankland, P. W. and Bontempi, B., 2005. The organization of recent and remote memories. Nat Rev Neurosci. 6,119-130.
Frassoni, C., Inverardi, F., Coco, S., Ortino, B., Grumelli, C., Pozzi, D., Verderio, C. and Matteoli, M., 2005. Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience. 131, 813-823.
Fuentes-Santamaria, V., Alvarado, J. C., Henkel, C. K. and Brunso-Bechtold, J. K., 2007. Cochlear ablation in adult ferrets results in changes in insulin-like growth factor-1 and synaptophysin immunostaining in the cochlear nucleus. Neuroscience. 148, 1033-1047.
Gerst, J. E., 2003. SNARE regulators: matchmakers and matchbreakers. Biochim Biophys Acta. 1641,99-110.
Gosso, M. F., de Geus, E. J., van Belzen, M. J., Polderman, T. J., Heutink, P., Boomsma, D. I. and Posthuma, D., 2006. The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts. Mol Psychiatry. 11,878-886.
Haas, K. Z., Sperber, E. F., Opanashuk, L. A., Stanton, P. K. and Moshe, S. L., 2001. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus. 11,615-625.
Hanaya, R., Boehm, N. and Nehlig, A., 2007. Dissociation of the immunoreactivity of synaptophysin and GAP-43 during the acute and latent phases of the lithium-pilocarpine model in the immature and adult rat. Exp Neurol. 204, 720-732.
Haut, S. R., Veliskova, J. and Moshe, S. L., 2004. Susceptibility of immature and adult brains to seizure effects. Lancet Neurol. 3,608-617.
Hermann, B. P., Seidenberg, M., Dow, C., Jones, J., Rutecki, P., Bhattacharya, A. and Bell, B., 2006. Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol. 60, 80-87.
Hinz, B., Becher, A., Mitter, D., Schulze, K., Heinemann, U., Draguhn, A. and Ahnert-Hilger, G., 2001. Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain. Eur J Cell Biol. 80, 615-619.
Hodel, A., 1998. Snap-25. Int J Biochem Cell Biol. 30,1069-1073.
Hou, Q., Gao, X., Zhang, X., Kong, L., Wang, X., Bian, W., Tu, Y., Jin,M., Zhao, G., Li, B., Jing, N. and Yu, L., 2004. SNAP-25 in hippocampal CA1 region is involved in memory consolidation. Eur J Neurosci. 20,1593-1603.
Hou, Q. L., Gao, X., Lu, Q., Zhang, X. H., Tu, Y. Y., Jin, M. L., Zhao, G. P., Yu, L., Jing, N. H. and Li, B. M., 2006. SNAP-25 in hippocampal CA3 region is required for long-term memory formation. Biochem Biophys Res Commun. 347, 955-962.
Jiang, Q., Wang, J., Wu, X. and Jiang, Y., 2007. Alterations of NR2B and PSD-95 expression after early-life epileptiform discharges in developing neurons. Int J Dev Neurosci. 25,165-170.
Koh, T. W. and Bellen, H. J., 2003. Synaptotagmin I, a Ca2+ sensor for neurotransmitter release. Trends Neurosci. 26,413-422.
Lee, C. L., Hannay, J., Hrachovy, R., Rashid, S., Antalffy, B. and Swann, J. W., 2001. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience. 107,71-84.
Liu, F. Y., Wang, X. F., Li, M. W., Li, J. M., Xi, Z. Q., Luan, G. M., Zhang, J. G., Wang, Y. P., Sun, J. J. and Li, Y. L., 2007. Upregulated expression of postsynaptic density-93 and N-methyl-D-aspartate receptors subunits 2B mRNA in temporal lobe tissue of epilepsy. Biochem Biophys Res Commun. 358, 825-830.
Looney, M. R., Dohan, F. C., Jr., Davies, K. G., Seidenberg, M., Hermann, B. P. and Schweitzer, J. B., 1999. Synaptophysin immunoreactivity in temporal lobe epilepsy-associated hippocampal sclerosis. Acta Neuropathol. 98,179-185.
Loscher, W., 2002. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res. 50,105-123.
Martin, S. J., Grimwood, P. D. and Morris, R. G., 2000. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci. 23,649-711.
McHugh, S. B., Deacon, R. M., Rawlins, J. N. and Bannerman, D. M., 2004. Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behav Neurosci. 118,63-78.
Morris, R., 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 11,47-60.
Niikura, Y., Abe, K. and Misawa, M., 2004. Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats. Brain Res. 1017,218-221.
Pauli, E., Hildebrandt, M., Romstock, J., Stefan, H. and Blumcke, I., 2006. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology. 67, 1383-1389.
Prut, L. and Belzung, C., 2003. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol. 463, 3-33.
Racine, R., Okujava, V. and Chipashvili, S., 1972. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol. 32, 295-299.
Reddy, P. H., Mani, G., Park, B. S., Jacques, J., Murdoch, G., Whetsell, W., Jr., Kaye, J. and Manczak, M., 2005. Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alzheimers Dis. 7, 103-117; discussion 173-180.
Roberts, L. A., Morris, B. J. and O'Shaughnessy, C. T., 1998. Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus. Neuroreport. 9, 33-36.
Sayin, U., Sutula, T. P. and Stafstrom, C. E., 2004. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia. 45,1539-1548.
Selkoe, D. J., 2002. Alzheimer's disease is a synaptic failure. Science. 298, 789-791.
Smith, T. D., Adams, M. M., Gallagher, M., Morrison, J. H. and Rapp, P. R., 2000. Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci. 20, 6587-6593.
Spellmann, I., Muller, N., Musil, R., Zill, P., Douhet, A., Dehning, S., Cerovecki, A., Bondy, B., Moller, H. J. and Riedel, M., 2008. Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci. 258, 335-344.
Stables, J. P., Bertram, E. H., White, H. S., Coulter, D. A., Dichter, M. A., Jacobs, M. P., Loscher, W., Lowenstein, D. H., Moshe, S. L., Noebels, J. L. and Davis, M., 2002. Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia. 43,1410-1420.
Su, H., Sochivko, D., Becker, A., Chen, J., Jiang, Y., Yaari, Y. and Beck, H., 2002. Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus. J Neurosci. 22, 3645-3655.
Sudhof, T. C., 2002. Synaptotagmins: why so many? J Biol Chem. 277, 7629-7632.
Suh, E. C., Jung, Y. J., Kim, Y. A., Park, E. M. and Lee, K. E., 2008. A beta 25-35 induces presynaptic changes in organotypic hippocampal slice cultures. Neurotoxicology. 29, 691-699.
Sutula, T., Lauersdorf, S., Lynch, M., Jurgella, C. and Woodard, A., 1995. Deficits in radial arm maze performance in kindled rats: evidence for long-lasting memory dysfunction induced by repeated brief seizures. J Neurosci. 15, 8295-8301.
Sze, C. I., Troncoso, J. C., Kawas, C., Mouton, P., Price, D. L. and Martin, L. J., 1997. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol. 56, 933-944.
Tocco, G., Bi, X., Vician, L., Lim, I. K., Herschman, H. and Baudry, M., 1996. Two synaptotagmin genes, Sytl and Syt4, are differentially regulated in adult brain and during postnatal development following kainic acid-induced seizures. Brain Res Mol Brain Res. 40,229-239.
Ullrich, B., Li, C., Zhang, J. Z., McMahon, H., Anderson, R. G., Geppert, M. and Sudhof, T. C., 1994. Functional properties of multiple synaptotagmins in brain. Neuron. 13, 1281-1291.
Veinbergs, I., Mante, M., Jung, M. W., Van Uden, E. and Masliah, E., 1999. Synaptotagmin and synaptic transmission alterations in apolipoprotein E-deficient mice. Prog Neuropsychopharmacol Biol Psychiatry. 23, 519-531.
Xiao, Z., Gong, Y., Wang, X. F., Xiao, F., Xi, Z. Q., Lu, Y. and Sun, H. B., 2008. Altered Expression of Synaptotagmin I In Temporal Lobe Tissue of Patients With Refractory Epilepsy.J Mol Neurosci.
Yang,J.W.,Czech,T.,Felizardo,M.,Baumgartner,C.and Lubec,G.,2006.Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy.Amino Acids.30,477-493.
Yin,S.,Guan,Z.,Tang,Y.,Zhao,J.,Hong,J.and Zhang,W.,2005.Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid.Brain Res.1053,195-202.
Zeng,K.,Wang,X.,Wang,Y.and Yan,Y.,2008.Enhanced Synaptic Vesicle Traffic in Hippocampus of Phenytoin-Resistant Kindled Rats.Neurochem Res.
Zhang,Y.,Vilaythong,A.P.,Yoshor,D.and Noebels,J.L.,2004.Elevated thalamic low-voltage-activated currents precede the onset of absence epilepsy in the SNAP25-deficient mouse mutant coloboma.J Neurosci.24,5239-5248.
Zhou,J.L.,Shatskikh,T.N.,Liu,X.and Holmes,G.L.,2007.Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures.Eur J Neurosci.25,3667-3677.
2.Huang L,Cilio MR,Silveira DC,et al.Long-term effects of neonatal seizures:a behavioral,electrophysiological,and histological study.Brain Res Dev Brain Res 1999;118(1-2):99-107.
3.Sayin U,Sutula TP,Stafstrom CE.Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety.Epilepsia 2004;45(12):1539-1548.
4.Gaitatzis A,Trimble MR,Sander JW.The psychiatric comorbidity of epilepsy.Acta Neurol Scand 2004;110(4):207-220.
5.Jokeit H,Ebner A.Long term effects of refractory temporal lobe epilepsy on cognitive abilities:a cross sectional study.J Neurol Neurosurg Psychiatry 1999;670):44-50.
6.Kwan P,Brodie MJ.Neuropsychological effects of epilepsy and antiepileptic drugs.Lancet 2001;357(9251):216-222.
7.Mula M,Trimble MR,Sander JW.The role of hippocampal sclerosis in topiramate-related depression and cognitive deficits in people with epilepsy.Epilepsia 2003;44(12):1573-1577.
8.Niikura Y,Abe K,Misawa M.Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats.Brain Res 2004;1017(1-2):218-221.
9. Dickson JM, Wilkinson ID, Howell SJ, Griffiths PD, Grunewald RA. Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy. J Neurol Neurosurg Psychiatry 2006; 77(7):834-840.
10. Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25(12):3667-3677.
11. Renaud J, Emond M, Meilleur S, Psarropoulou C, Carmant L. AIDA, a class I metabotropic glutamate-receptor antagonist limits kainate-induced hippocampal dysfunction. Epilepsia 2002; 43(11):1306-1317.
12. Lynch M, Sayin U, Golarai G, Sutula T. NMDA receptor-dependent plasticity of granule cell spiking in the dentate gyrus of normal and epileptic rats. J Neurophysiol 2000; 84(6):2868-2879.
13. Heynen AJ, Bear MR Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo. J Neurosci 2001; 21(24):9801-9813.
14. Li S, Anwyl R, Rowan MJ. A persistent reduction in short-term facilitation accompanies long-term potentiation in the CA1 area in the intact hippocampus. Neuroscience 2000; 100(2):213-220.
15. Hannesson DK, Wallace AE, Pollock M, Corley S, Mohapel P, Corcoran ME. The relation between extent of dorsal hippocampal kindling and delayed-match-to-place performance in the Morris water maze. Epilepsy Res 2004; 58(2-3): 145-154.
16. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401(6748):63-69.
17. Henshall DC, Chen J, Simon RP. Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. J Neurochem 2000; 74(3): 1215-1223.
18. Bragin A, Wilson CL, Engel J, Jr. Rate of interictal events and spontaneous seizures in epileptic rats after electrical stimulation of hippocampus and its afferents. Epilepsia 2002; 43 Suppl 5:81-85.
19. McMahon HT, Bolshakov VY, Janz R, Hammer RE, Siegelbaum SA, Sudhof TC. Synaptophysin, a major synaptic vesicle protein, is not essential for neurotransmitter release. Proc Natl Acad Sci U S A 1996; 93(10):4760-4764.
20. Janz R, Sudhof TC, Hammer RE, Unni V, Siegelbaum SA, Bolshakov VY. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 1999; 24(3):687-700.
21. Mullany PM, Lynch MA. Evidence for a role for synaptophysin in expression of long-term potentiation in rat dentate gyms. Neuroreport 1998; 9(11):2489-2494.
22. Mullany P, Lynch MA. Changes in protein synthesis and synthesis of the synaptic vesicle protein, synaptophysin, in entorhinal cortex following induction of long-term potentiation in dentate gyms: an age-related study in the rat. Neuropharmacology 1997; 36(7):973-980.
23. Chen YC, Chen QS, Lei JL, Wang SL. Physical training modifies the age-related decrease of GAP-43 and synaptophysin in the hippocampal formation in C57BL/6J mouse. Brain Res 1998; 806(2):238-245.
24. Selkoe DJ. Alzheimer's disease is a synaptic failure. Science 2002; 298(5594):789-791.
25. Suh EC, Jung YJ, Kim YA, Park EM, Lee KE. A beta 25-35 induces presynaptic changes in organotypic hippocampal slice cultures. Neurotoxicology 2008; 29(4):691-699.
26. Geddes JW, Hess EJ, Hart RA, Kesslak JP, Cotman CW, Wilson MC. Lesions of hippocampal circuitry define synaptosomal-associated protein-25 (SNAP-25) as a novel presynaptic marker. Neuroscience 1990; 38(2):515-525.
27. Oyler GA, Polli JW, Higgins GA, Wilson MC, Billingsley ML. Distribution and expression of SNAP-25 immunoreactivity in rat brain, rat PC-12 cells and human SMS-KCNR neuroblastoma cells. Brain Res Dev Brain Res 1992; 65(2):133-146.
28. Mehta PP, Battenberg E, Wilson MC. SNAP-25 and synaptotagmin involvement in the final Ca(2+)-dependent triggering of neurotransmitter exocytosis. Proc Natl Acad Sci U S A 1996; 93(19): 10471-10476.
29. Banerjee A, Kowalchyk JA, DasGupta BR, Martin TF. SNAP-25 is required for a late postdocking step in Ca2+-dependent exocytosis. J Biol Chem 1996; 271(34):20227-20230.
30. Jahn R, Lang T, Sudhof TC. Membrane fusion. Cell 2003; 112(4):519-533.
31. Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci 2004; 27:509-547.
32. Roberts LA, Morris BJ, O'Shaughnessy CT. Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus. Neuroreport 1998; 9(1):33-36.
33. Hou Q, Gao X, Zhang X, et al. SNAP-25 in hippocampal CA1 region is involved in memory consolidation. Eur J Neurosci 2004; 20(6): 1593-1603.
34. Hou QL, Gao X, Lu Q, et al. SNAP-25 in hippocampal CA3 region is required for long-term memory formation. Biochem Biophys Res Commun 2006; 347(4):955-962.
35. Gosso MF, de Geus EJ, van Belzen MJ, et al. The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts. Mol Psychiatry 2006; 11(9):878-886.
36. Spellmann I, Muller N, Musil R, et al. Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci 2008; 258(6):335-344.
37. Fukuda M. Molecular cloning and characterization of human, rat, and mouse synaptotagmin XV. Biochem Biophys Res Commun 2003; 306(1):64-71.
38. Fernandez-Chacon R, Konigstorfer A, Gerber SH, et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 2001; 410(6824):41-49.
39. Sudhof TC. Synaptotagmins: why so many? J Biol Chem 2002; 277(10):7629-7632.
40. Koh TW, Bellen HJ. Synaptotagmin I, a Ca2+ sensor for neurotransmitter release. Trends Neurosci 2003; 26(8):413-422.
41. Chen GH, Wang YJ, Qin S, Yang QG, Zhou JN, Liu RY. Age-related spatial cognitive impairment is correlated with increase of synaptotagmin 1 in dorsal hippocampus in SAMP8 mice. Neurobiol Aging 2007; 28(4):611-618.
42. Reddy PH, Mani G, Park BS, et al. Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alzheimers Dis 2005; 7(2):103-117; discussion 173-180.
43. Hanaya R, Boehm N, Nehlig A. Dissociation of the immunoreactivity of synaptophysin and GAP-43 during the acute and latent phases of the lithium-pilocarpine model in the immature and adult rat. Exp Neurol 2007; 204(2):720-732.
44. Zhang Y, Vilaythong AP, Yoshor D, Noebels JL. Elevated thalamic low-voltage-activated currents precede the onset of absence epilepsy in the SNAP25-deficient mouse mutant coloboma. J Neurosci 2004; 24(22):5239-5248.
45. Xiao Z, Gong Y, Wang XF, et al. Altered Expression of Synaptotagmin I In Temporal Lobe Tissue of Patients With Refractory Epilepsy. J Mol Neurosci 2008.
46. Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol 1972; 32(3):295-299.
47. Adams SV, Winterer J, Muller W. Muscarinic signaling is required for spike-pairing induction of long-term potentiation at rat Schaffer collateral-CA1 synapses. Hippocampus 2004; 14(4):413-416.
48. Lee JI, Ahnn J. Calcineurin in animal behavior. Mol Cells 2004; 17(3):390-396.
49. Blank T, Nijholt I, Kye MJ, Spiess J. Small conductance Ca2+-activated K+ channels as targets of CNS drug development. Curr Drug Targets CNS Neurol Disord 2004;3(3):161-167.
50. Tseng KY, O'Donnell P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 2004; 24(22):5131-5139.
51. Moyano S, Frechilla D, Del Rio J. NMDA receptor subunit and CaMKII changes in rat hippocampus induced by acute MDMA treatment: a mechanism for learning impairment. Psychopharmacology (Berl) 2004; 173(3-4):337-345.
52. Beck H, Goussakov IV, Lie A, Helmstaedter C, Elger CE. Synaptic plasticity in the human dentate gyrus. J Neurosci 2000; 20(18):7080-7086.
53. Okada T, Yamada N, Tsuzuki K, Horikawa HP, Tanaka K, Ozawa S. Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning. Eur J Neurosci 2003; 17(2):341-349.
54. Stanton PK, Gage AT. Distinct synaptic loci of Ca2+/calmodulin-dependent protein kinase II necessary for long-term potentiation and depression. J Neurophysiol 1996; 76(3):2097-2101.
55. Hannesson DK, Mohapel P, Corcoran ME. Dorsal hippocampal kindling selectively impairs spatial learning/short-term memory. Hippocampus 2001; ll(3):275-286.
56. Leung LS, Wu C. Kindling suppresses primed-burst-induced long-term potentiation in hippocampal CA1. Neuroreport 2003; 14(2):211-214.
57. Sudhof TC, Lottspeich F, Greengard P, Mehl E, Jahn R. The cDNA and derived amino acid sequences for rat and human synaptophysin. Nucleic Acids Res 1987; 15(22):9607.
58. Pang DT, Wang JK, Valtorta F, Benfenati F, Greengard P. Protein tyrosine phosphorylation in synaptic vesicles. Proc Natl Acad Sci U S A 1988; 85(3):762-766.
59. Rubenstein JL, Greengard P, Czernik AJ. Calcium-dependent serine phosphorylation of synaptophysin. Synapse 1993; 13(2): 161-172.
60. Shaw GM, Wasserman CR, Lammer EJ, et al. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 1996; 58(3):551-561.
61. Wiedenmann B, Franke WW. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 1985; 41(3):1017-1028.
62. Daly C, Sugimori M, Moreira JE, Ziff EB, Llinas R. Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles. Proc Natl Acad Sci U S A 2000;97(11):6120-6125.
63. Daly C, Ziff EB. Ca2+-dependent formation of a dynamin-synaptophysin complex: potential role in synaptic vesicle endocytosis. J Biol Chem 2002; 277(11):9010-9015.
64. Tarsa L, Goda Y. Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 2002; 99(2):1012-1016.
65. Looney MR, Dohan FC, Jr., Davies KG, Seidenberg M, Hermann BP, Schweitzer JB. Synaptophysin immunoreactivity in temporal lobe epilepsy-associated hippocampal sclerosis. Acta Neuropathol 1999; 98(2):179-185.
66. Heffeman JM, Eastwood SL, Nagy Z, Sanders MW, McDonald B, Harrison PJ. Temporal cortex synaptophysin mRNA is reduced in Alzheimer's disease and is negatively correlated with the severity of dementia. Exp Neurol 1998; 150(2):235-239.
67. Callahan LM, Vaules WA, Coleman PD. Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol 1999; 58(3):275-287.
68. Landen M, Davidsson P, Gottfries CG, Grenfeldt B, Stridsberg M, Blennow K. Reduction of the small synaptic vesicle protein synaptophysin but not the large dense core chromogranins in the left thalamus of subjects with schizophrenia. Biol Psychiatry 1999; 46(12):1698-1702.
69. Eastwood SL, Harrison PJ. Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections. Neuroscience 1999; 93(1):99-106.
70. Karson CN, Mrak RE, Schluterman KO, Sturner WQ, Sheng JG, Griffin WS. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'. Mol Psychiatry 1999; 4(1):39-45.
71. Glantz LA, Austin MC, Lewis DA. Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 2000; 48(5):389-397.
72. Sollner T, Whiteheart SW, Brunner M, et al. SNAP receptors implicated in vesicle targeting and fusion. Nature 1993; 362(6418):318-324.
73. Low P, Norlin T, Risinger C, et al. Inhibition of neurotransmitter release in the lamprey reticulospinal synapse by antibody-mediated disruption of SNAP-25 function. Eur J Cell Biol 1999; 78(11):787-793.
74. Duc C, Catsicas S. Ultrastructural localization of SNAP-25 within the rat spinal cord and peripheral nervous system. J Comp Neurol 1995; 356(1):152-163.
75. Grosse G, Grosse J, Tapp R, et al. SNAP-25 requirement for dendritic growth of hippocampal neurons. J Neurosci Res 1999; 56(5):539-546.
76. Lan JY, Skeberdis VA, Jover T, Zheng X, Bennett MV, Zukin RS. Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking. J Neurosci 2001; 21(16):6058-6068.
77. Osen-Sand A, Catsicas M, Staple JK, et al. Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature 1993; 364(6436):445-448.
78. Shirasu M, Kimura K, Kataoka M, et al. VAMP-2 promotes neurite elongation and SNAP-25A increases neurite sprouting in PC12 cells. Neurosci Res 2000; 37(4):265-275.
79. Braun JE, Madison DV. A novel SNAP25-caveolin complex correlates with the onset of persistent synaptic potentiation. J Neurosci 2000; 20(16):5997-6006.
80. Steffensen SC, Wilson MC, Henriksen SJ. Coloboma contiguous gene deletion encompassing Snap alters hippocampal plasticity. Synapse 1996; 22(3):281-289.
81. Tucker WC, Chapman ER. Role of synaptotagmin in Ca2+-triggered exocytosis. Biochem J 2002; 366(Pt 1):1-13.
82. Weimer RM, Jorgensen EM. Controversies in synaptic vesicle exocytosis. J Cell Sci 2003; 116(Pt 18):3661-3666.
83. Li L, Chin LS. The molecular machinery of synaptic vesicle exocytosis. Cell Mol Life Sci 2003; 60(5):942-960.
84. Stevens CF, Sullivan JM. The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission. Neuron 2003; 39(2):299-308.
85. Wang CT, Lu JC, Bai J, et al. Different domains of synaptotagmin control the choice between kiss-and-run and full fusion. Nature 2003; 424(6951):943-947.
86. Littleton JT, Bai J, Vyas B, et al. synaptotagmin mutants reveal essential functions for the C2B domain in Ca2+-triggered fusion and recycling of synaptic vesicles in vivo. J Neurosci 2001; 21(5): 1421-1433.
87. Nicholson-Tomishima K, Ryan TA. Kinetic efficiency of endocytosis at mammalian CNS synapses requires synaptotagmin I. Proc Natl Acad Sci U S A2004; 101(47):16648-16652.
88. Poskanzer KE, Marek KW, Sweeney ST, Davis GW. Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo. Nature 2003; 426(6966):559-563.
89. Rickman C, Davletov B. Mechanism of calcium-independent synaptotagmin binding to target SNAREs. J Biol Chem 2003; 278(8):5501-5504.
90. Bai J, Chapman ER. The C2 domains of synaptotagmin--partners in exocytosis. Trends Biochem Sci 2004; 29(3): 143-151.
91. Masliah E, Mallory M, Alford M, et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology 2001; 56(1):127-129.
92. Sze CI, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ. Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains. J Neurol Sci 2000; 175(2):81-90.
93. Takamori M. Lambert-Eaton myasthenic syndrome as an autoimmune calcium channelopathy. Biochem Biophys Res Commun 2004; 322(4):1347-1351.
94. Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51(1):41-48.
95. Yin S, Guan Z, Tang Y, Zhao J, Hong J, Zhang W. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005; 1053(1-2):195-202.
96. Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67(8): 1383-1389.
97. Lee CL, Hannay J, Hrachovy R, Rashid S, Antalffy B, Swann JW. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 2001; 107(1):71-84.
98. Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 2003; 54(6):706-718.
99. Su SW, Cilio MR, Sogawa Y, Silveira DC, Holmes GL, Stafstrom CE. Timing of ketogenic diet initiation in an experimental epilepsy model. Brain Res Dev Brain Res 2000; 125(1-2):131-138.
100. Haas KZ, Sperber EF, Opanashuk LA, Stanton PK, Moshe SL. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus 2001; 11(6):615-625.
101. Chen LS, Wong JG, Banerjee PK, Snead OC, 3rd. Kainic acid-induced focal cortical seizure is associated with an increase of synaptophysin immunoreactivity in the cortex. Exp Neurol 1996; 141(1):25-31.
102. Costantin L, Bozzi Y, Richichi C, et al. Antiepileptic effects of botulinum neurotoxin E.J Neurosci 2005;25(8):1943-1951.
103.Yang JW,Czech T,Felizardo M,Baumgartner C,Lubec G.Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy.Amino Acids 2006;30(4):477-493.
104.Frankland PW,Bontempi B.The organization of recent and remote memories.Nat Rev Neurosci 2005;6(2):119-130.
1. Austin JK, Dunn DW. Progressive behavioral changes in children with epilepsy. Prog Brain Res 2002; 135:419-427.
2. Huang L, Cilio MR, Silveira DC, et al. Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Brain Res Dev Brain Res 1999;118(1-2):99-107.
3. Sayin U, Sutula TP, Stafstrom CE. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 2004; 45(12):1539-1548.
4. Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004; 110(4):207-220.
5. Jokeit H, Ebner A. Long term effects of refractory temporal lobe epilepsy on cognitive abilities: a cross sectional study. J Neurol Neurosurg Psychiatry 1999; 67(1):44-50.
6. Niikura Y, Abe K, Misawa M. Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats. Brain Res 2004; 1017(1-2):218-221.
7. Renaud J, Emond M, Meilleur S, Psarropoulou C, Carmant L. AIDA, a class I metabotropic glutamate-receptor antagonist limits kainate-induced hippocampal dysfunction. Epilepsia 2002; 43(11):1306-1317.
8. Teyler TJ, DiScenna P. Long-term potentiation. Annu Rev Neurosci 1987; 10:131-161.
9. Yamakura T, Shimoji K. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog Neurobiol 1999; 59(3):279-298.
10. Esplugues JV. NO as a signalling molecule in the nervous system. Br J Pharmacol 2002; 135(5): 1079-1095.
11. Katzoff A, Ben-Gedalya T, Susswein AJ. Nitric oxide is necessary for multiple memory processes after learning that a food is inedible in aplysia. J Neurosci 2002; 22(21):9581-9594.
12. Meyer RC, Spangler EL, Kametani H, Ingram DK. Age-associated memory impairment. Assessing the role of nitric oxide. Ann N Y Acad Sci 1998; 854:307-317.
13. Paul V, Reddy L, Ekambaram P. Prevention of picrotoxin convulsions-induced learning and memory impairment by nitric oxide increasing dose of L-arginine in rats. Pharmacol Biochem Behav 2003; 75(2):329-334.
14. Wu J, Huang KP, Huang FL. Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+- and Ca2+/calmodulin-dependent neuronal signaling in the hippocampus. J Neurochem 2003; 86(6): 1524-1533.
15. Mishina M, Mori H, Araki K, et al. Molecular and functional diversity of the NMDA receptor channel. Ann N Y Acad Sci 1993; 707:136-152.
16. Sakimura K, Kutsuwada T, Ito I, et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 1995; 373(6510):151-155.
17. Kiyama Y, Manabe T, Sakimura K, Kawakami F, Mori H, Mishina M. Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilonl subunit. J Neurosci 1998; 18(17):6704-6712.
18. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401(6748):63-69.
19. Kennedy MB. Signal-processing machines at the postsynaptic density. Science 2000; 290(5492):750-754.
20. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 1995; 269(5231):1737-1740.
21. Nusser Z, Mulvihill E, Streit P, Somogyi P. Subsynaptic segregation of metabotropic and ionotropic glutamate receptors as revealed by immunogold localization. Neuroscience 1994; 61(3):421-427.
22. Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998; 396(6710):433-439.
23. Brandt C, Gastens AM, Sun M, Hausknecht M, Loscher W. Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology 2006; 51(4):789-804.
24. Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy. J Neurosci 2002; 22(14):6052-6061.
25. Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol 1972; 32(3):295-299.
26. Duprat F, Daw M, Lim W, Collingridge G, Isaac J. GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 2003; 358(1432):715-720.
27. Watt AJ, Sjostrom PJ, Hausser M, Nelson SB, Turrigiano GG.A proportional but slower NMDA potentiation follows AMPA potentiation in LTP. Nat Neurosci 2004; 7(5):518-524.
28. Taverna FA, Georgiou J, McDonald RJ, et al. Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation. J Physiol 2005; 565(Pt 2):579-591.
29. Erreger K, Dravid SM, Banke TG, Wyllie DJ, Traynelis SF. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J Physiol 2005; 563(Pt 2):345-358.
30. Woodside BL, Borroni AM, Hammonds MD, Teyler TJ. NMDA receptors and voltage-dependent calcium channels mediate different aspects of acquisition and retention of a spatial memory task. Neurobiol Learn Mem 2004; 81(2):105-114.
31. Clayton DA, Mesches MH, Alvarez E, Bickford PC, Browning MD. A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 2002; 22(9):3628-3637.
32. O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES. AMPA receptor potentiators for the treatment of CNS disorders. Curr Drug Targets CNS Neurol Disord 2004; 3(3):181-194.
33. Sessoms-Sikes S, Honse Y, Lovinger DM, Colbran RJ. CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism. Mol Cell Neurosci 2005; 29(1):139-147.
34. Rosenblum K, Futter M, Voss K, et al. The role of extracellular regulated kinases I/II in late-phase long-term potentiation. J Neurosci 2002; 22(13):5432-5441.
35. Poommipanit PB, Chen B, Oltvai ZN. Interleukin-3 induces the phosphorylation of a distinct fraction of bcl-2. J Biol Chem 1999; 274(2): 1033-1039.
36. Lonart G.RIM1: an edge for presynaptic plasticity. Trends Neurosci 2002; 25(7):329-332.
37. Lennmyr F, Karlsson S, Gerwins P, Ata KA, Terent A. Activation of mitogen-activated protein kinases in experimental cerebral ischemia. Acta Neurol Scand 2002; 106(6):333-340.
38. Chien WL, Liang KC, Teng CM, Kuo SC, Lee FY, Fu WM. Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1. Eur J Neurosci 2005; 21 (6): 1679-1688.
39. Yuan LL, Adams JP, Swank M, Sweatt JD, Johnston D. Protein kinase modulation of dendritic K+ channels in hippocampus involves a mitogen-activated protein kinase pathway. J Neurosci 2002; 22(12):4860-4868.
40. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361(6407):31-39.
41. Behe P, Stern P, Wyllie DJ, Nassar M, Schoepfer R, Colquhoun D. Determination of NMDA NR1 subunit copy number in recombinant NMDA receptors. Proc Biol Sci 1995; 262(1364):205-213.
42. Premkumar LS, Auerbach A. Stoichiometry of recombinant N-methyl-D-aspartate receptor channels inferred from single-channel current patterns. J Gen Physiol 1997; 110(5):485-502.
43. Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA. Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 1995; 15(10):6498-6508.
44. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51(1):7-61.
45. Lieberman DN, Mody I. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 1994; 369(6477):235-239.
46. Omkumar RV, Kiely MJ, Rosenstein AJ, Min KT, Kennedy MB. Identification of a phosphorylation site for calcium/calmodulindependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 1996; 271(49):31670-31678.
47. Kuner T, Wollmuth LP, Karlin A, Seeburg PH, Sakmann B. Structure of the NMDA receptor channel M2 segment inferred from the accessibility of substituted cysteines. Neuron 1996; 17(2):343-352.
48. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994; 12(3):529-540.
49. Kutsuwada T, Sakimura K, Manabe T, et al. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 1996; 16(2):333-344.
50. Thompson CL, Drewery DL, Atkins HD, Stephenson FA, Chazot PL. Immunohistochemical localization of N-methyl-D-aspartate receptor NR1, NR2A, NR2B and NR2C/D subunits in the adult mammalian cerebellum. Neurosci Lett 2000; 283(2):85-88.
51. Charton JP, Herkert M, Becker CM, Schroder H. Cellular and subcellular localization of the 2B-subunit of the NMDA receptor in the adult rat telencephalon. Brain Res 1999; 816(2):609-617.
52. Momiyama A. Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord. J Physiol 2000; 523 Pt 3:621-628.
53. Scheetz AJ, Constantine-Paton M. Modulation of NMDA receptor function: implications for vertebrate neural development. Faseb J 1994; 8(10):745-752.
54. Tovar KR, Westbrook GL. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 1999; 19(10):4180-4188.
55. Sasner M, Buonanno A. Distinct N-methyl-D-aspartate receptor 2B subunit gene sequences confer neural and developmental specific expression. J Biol Chem 1996; 271(35):21316-21322.
56. Klein M, Pieri I, Uhlmann F, Pfizenmaier K, Eisel U. Cloning and characterization of promoter and 5'-UTR of the NMDA receptor subunit epsilon 2: evidence for alternative splicing of 5'-non-coding exon. Gene 1998; 208(2):259-269.
57. Matus A. Actin-based plasticity in dendritic spines. Science 2000; 290(5492):754-758.
58. Okabe S, Miwa A, Okado H. Spine formation and correlated assembly of presynaptic and postsynaptic molecules. J Neurosci 2001; 21(16):6105-6114.
59. Lendvai B, Stern EA, Chen B, Svoboda K. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Nature 2000; 404(6780):876-881.
60. Ziv NE, Garner CC. Principles of glutamatergic synapse formation: seeing the forest for the trees. Curr Opin Neurobiol 2001; 11(5):536-543.
61. Baker KB, Kim JJ. Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats. Learn Mem 2002; 9(2):58-65.
62. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS. PSD-95 involvement in maturation of excitatory synapses. Science 2000; 290(5495): 1364-1368.
63. Roche KW, Standley S, McCallum J, Dune Ly C, Ehlers MD, Wenthold RJ. Molecular determinants of NMDA receptor internalization. Nat Neurosci 2001; 4(8):794-802.
64. Carroll RC, Beattie EC, von Zastrow M, Malenka RC. Role of AMPA receptor endocytosis in synaptic plasticity. Nat Rev Neurosci 2001; 2(5):315-324.
65. Steigerwald F, Schulz TW, Schenker LT, Kennedy MB, Seeburg PH, Kohr G. C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors. J Neurosci 2000; 20(12):4573-4581.
66. Barria A, Malinow R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 2002; 35(2):345-353.
67. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002; 5(5):405-414.
68. Fong DK, Rao A, Crump FT, Craig AM. Rapid synaptic remodelmg by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II. J Neurosci 2002; 22(6):2153-2164.
69. Clayton DA, Browning MD. Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats. Neurobiol Aging 2001; 22(1):165-168.
70. Shimizu E, Tang YP, Rampon C, Tsien JZ. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 2000; 290(5494): 1170-1174.
71. Turchi J, Sarter M. Antisense oligodeoxynucleotide-induced suppression of basal forebrain NMDA-NR1 subunits selectively impairs visual attentional performance in rats. Eur J Neurosci 2001; 14(1):103-117.
72. Ito I, Kawakami R, Sakimura K, Mishina M, Sugiyama H. Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses. Neuropharmacology 2000; 39(6):943-951.
73. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T. Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor epsilonl subunit. J Neurosci 2001; 21(2):750-757.
74. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T. Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor epsilon 4 subunit. J Neurosci 2002; 22(6):2335-2342.
75. Lee I, Kesner RP. Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory. Nat Neurosci 2002; 5(2):162-168.
76. Sheng M. The postsynaptic NMDA-receptor--PSD-95 signaling complex in excitatory synapses of the brain. J Cell Sci 2001; 114(Pt 7):1251.
77. Lin Y, Skeberdis VA, Francesconi A, Bennett MV, Zukin RS. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 2004; 24(45):10138-10148.
78. Dong YN, Waxman EA, Lynch DR. Interactions of postsynaptic density-95 and the NMDA receptor 2 subunit control calpain-mediated cleavage of the NMDA receptor. J Neurosci 2004; 24(49):11035-11045.
79. Losi G, Prybylowski K, Fu Z, Luo J, Wenthold RJ, Vicini S. PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat. J Physiol 2003; 548(Pt l):21-29.
80. Li B, Otsu Y, Murphy TH, Raymond LA. Developmental decrease in NMDA receptor desensitization associated with shift to synapse and interaction with postsynaptic density-95. J Neurosci 2003; 23(35): 11244-11254.
81. Colledge M, Dean RA, Scott GK, Langeberg LK, Huganir RL, Scott JD. Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 2000;27(1):107-119.
82. Yan XB, Song B, Zhang GY. Postsynaptic density protein 95 mediates Ca2+/calmodulin-dependent protein kinase II-activated serine phosphorylation of neuronal nitric oxide synthase during brain ischemia in rat hippocampus. Neurosci Lett 2004; 355(3): 197-200.
83. Christopherson KS, Hillier BJ, Lim WA, Bredt DS. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 1999; 274(39):27467-27473.
84. Brenman JE, Chao DS, Gee SH, et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alphal-syntrophin mediated by PDZ domains. Cell 1996; 84(5):757-767.
85. Ishii H, Shibuya K, Ohta Y, et al. Enhancement of nitric oxide production by association of nitric oxide synthase with N-methyl-D-aspartate receptors via postsynaptic density 95 in genetically engineered Chinese hamster ovary cells: real-time fluorescence imaging using nitric oxide sensitive dye. J Neurochem 2006; 96(6): 1531-1539.
86. Stein V, House DR, Bredt DS, Nicoll RA. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression. J Neurosci 2003; 23(13):5503-5506.
87. Wyneken U, Marengo JJ, Villanueva S, et al. Epilepsy-induced changes in signaling systems of human and rat postsynaptic densities. Epilepsia 2003; 44(2):243-246.
88. Wyneken U, Smalla KH, Marengo JJ, et al. Kainate-induced seizures alter protein composition and N-methyl-D-aspartate receptor function of rat forebrain postsynaptic densities. Neuroscience 2001; 102(1):65-74.
89. Nakazawa T, Tezuka T, Yamamoto T. [Regulation of NMDA receptor function by Fyn-mediated tyrosine phosphorylation]. Nihon Shinkei Seishin Yakurigaku Zasshi 2002; 22(5): 165-167.
90. Colledge M, Snyder EM, Crozier RA, et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 2003; 40(3):595-607.
91. Aarts M, Liu Y, Liu L, et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 2002; 298(5594):846-850.
92. Savinainen A, Garcia EP, Dorow D, Marshall J, Liu YF. Kainate receptor activation induces mixed lineage kinase-mediated cellular signaling cascades via post-synaptic density protein 95.J Biol Chem 2001;276(14):11382-11386.
93.Pei DS,Wang XT,Liu Y,et al.Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence.Brain 2006;129(Pt 2):465-479.
94.Hou XY,Zhang GY,Wang DG,Guan QH,Yan JZ.Suppression of postsynaptic density protein 95 by antisense oligonucleotides diminishes postischemic pyramidal cell death in rat hippocampal CA1 subfield.Neurosci Lett 2005;385(3):230-233.
95.Pei DS,Sun YF,Guan QH,Hao ZB,Xu TL,Zhang GY.Postsynaptic density protein 95 antisense oligodeoxynucleotides inhibits the activation of MLK3and JNK3 via the GluR6.PSD-95.MLK3 signaling module after transient cerebral ischemia in rat hippocampus.Neurosci Lett 2004;367(1):71-75.
96.Gylys KH,Fein JA,Yang F,Wiley DJ,Miller CA,Cole GM.Synaptic changes in Alzheimer's disease:increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence.Am J Pathol 2004;165(5):1809-1817.
97.Kelly BL,Ferreira A.beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons.J Biol Chem 2006;281(38):28079-28089.
98.Yao M,Nguyen TV,Pike CJ.Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w.J Neurosci 2005;25(5):1149-1158.
99.Morishima Y,Gotoh Y,Zieg J,et al.Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand.J Neurosci 2001;21(19):7551-7560.
100.Lee ST,Kim M.Aging and neurodegeneration.Molecular mechanisms of neuronal loss in Huntington's disease.Mech Ageing Dev 2006;127(5):432-435.
101.Kajimoto Y,Shirakawa O,Lin XH,et al.Synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP) is expressed differentially in phencyclidine-treated rats and is increased in the nucleus accumbens of patients with schizophrenia. Neuropsychopharmacology 2003; 28(10):1831-1839.
102. Bao J, Lin H, Ouyang Y, et al. Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nat Neurosci 2004; 7(11):1250-1258.
103. Hahn CG, Wang HY, Cho DS, et al. Altered neuregulin l-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006; 12(7):824-828.
104. Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51(1):41-48.
105. Yin S, Guan Z, Tang Y, Zhao J, Hong J, Zhang W. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005; 1053(1-2):195-202.
106. Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67(8):1383-1389.
107. Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25(12):3667-3677.
108. Lee CL, Hannay J, Hrachovy R, Rashid S, Antalffy B, Swann JW. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 2001; 107(1):71-84.
109. Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 2003; 54(6):706-718.
110. Su SW, Cilio MR, Sogawa Y, Silveira DC, Holmes GL, Stafstrom CE. Timing of ketogenic diet initiation in an experimental epilepsy model. Brain Res Dev Brain Res 2000;125(1-2):131-138.
111.Haas KZ,Sperber EF,Opanashuk LA,Stanton PK,Moshe SL.Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling.Hippocampus 2001;11(6):615-625.
112.Frankland PW,Bontempi B.The organization of recent and remote memories.Nat Rev Neurosci 2005;6(2):119-130.
[1] Stables JP, Bertram EH, White HS, et al. Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia 2002; 43:1410-1420.
[2] Austin JK, Dunn DW. Progressive behavioral changes in children with epilepsy. Prog Brain Res 2002; 135:419-427.
[3] Huang L, Cilio MR, Silveira DC, et al. Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Brain Res Dev Brain Res 1999; 118:99-107.
[4] Sayin U, Sutula TP, Stafstrom CE. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 2004; 45:1539-1548.
[5] Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004; 110:207-220.
[6] Jokeit H, Ebner A. Long term effects of refractory temporal lobe epilepsy on cognitive abilities: a cross sectional study. J Neurol Neurosurg Psychiatry 1999; 67:44-50.
[7] Loscher W. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res 2002; 50:105-123.
[8] Nadler JV. Minireview. Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 1981; 29:2031-2042.
[9] Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51:41-48.
[10]Becker A, Letzel K, Letzel U, Grecksch G. Kindling of the dorsal and the ventral hippocampus: effects on learning performance in rats. Physiol Behav 1997; 62:1265-1271.
[11]Haut SR, Veliskova J, Moshe SL. Susceptibility of immature and adult brains to seizure effects. Lancet Neurol 2004; 3:608-617.
[12]Sutula T, Lauersdorf S, Lynch M, Jurgella C, Woodard A. Deficits in radial arm maze performance in kindled rats: evidence for long-lasting memory dysfunction induced by repeated brief seizures. JNeurosci 1995; 15:8295-8301.
[13]Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 1999; 399:66-70.
[14]Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25:3667-3677.
[15]Calabresi P, Saulle E, Centonze D, Pisani A, Marfia GA, Bernardi G. Post-ischaemic long-term synaptic potentiation in the striatum: a putative mechanism for cell type-specific vulnerability. Brain 2002; 125:844-860.
[16]McBain CJ, Mayer ML. N-methyl-D-aspartic acid receptor structure and function. Physiol Rev 1994; 74:723-760.
[17]Loftis JM, Janowsky A. The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther 2003; 97:55-85.
[18]Riedel G. Function of metabotropic glutamate receptors in learning and memory. Trends Neurosci 1996; 19:219-224.
[19]Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH. Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 1997; 51:23-32.
[20]Gardoni F, Schrama LH, Kamal A, Gispen WH, Cattabeni F, Di Luca M. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor. J Neurosci 2001; 21:1501 -1509.
[21]Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998; 396:433-439.
[22]Pollak DD, Herkner K, Hoeger H, Lubec G. Behavioral testing upregulates pCaMKII, BDNF, PSD-95 and egr-1 in hippocampus of FVB/N mice. Behav Brain Res 2005; 163:128-135.
[23]Nyffeler M, Zhang WN, Feldon J, Knuesel I. Differential expression of PSD proteins in age-related spatial learning impairments. Neurobiol Aging 2007; 28:143-155.
[24]Waxman EA, Lynch DR. N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist 2005; 11:37-49.
[25]Kennedy MB. Signal-processing machines at the postsynaptic density. Science 2000; 290:750-754.
[26]Williams JM, Guevremont D, Kennard JT, Mason-Parker SE, Tate WP, Abraham WC. Long-term regulation of N-methyl-D-aspartate receptor subunits and associated synaptic proteins following hippocampal synaptic plasticity. Neuroscience 2003; 118:1003-1013.
[27]Jiang Q, Wang J, Wu X, Jiang Y. Alterations of NR2B and PSD-95 expression after early-life epileptiform discharges in developing neurons. Int J Dev Neurosci 2007; 25:165-170.
[28]Brandt C, Gastens AM, Sun M, Hausknecht M, Loscher W. Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology 2006; 51:789-804.
[29]Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy. J Neurosci 2002; 22:6052-6061.
[30]Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol 1972; 32:295-299.
[31]Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 2003; 463:3-33.
[32]Liu FY, Wang XF, Li MW, et al. Upregulated expression of postsynaptic density-93 and N-methyl-D-aspartate receptors subunits 2B mRNA in temporal lobe tissue of epilepsy. Biochem Biophys Res Commun 2007; 358:825-830.
[33] Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11:47-60.
[34] Yin S, Guan Z, Tang Y, Zhao J, Hong J, Zhang W. Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid. Brain Res 2005; 1053:195-202.
[35]Pauli E, Hildebrandt M, Romstock J, Stefan H, Blumcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67:1383-1389.
[36] Lee CL, Hannay J, Hrachovy R, Rashid S, Antalffy B, Swann JW. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 2001; 107:71-84.
[37]Chang YC, Huang AM, Kuo YM, Wang ST, Chang YY, Huang CC. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol 2003; 54:706-718.
[38]Haas KZ, Sperber EF, Opanashuk LA, Stanton PK, Moshe SL. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus 2001; 11:615-625.
[39]Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci 2005; 6:119-130.
[40]Gultekin F, Karakoyun I, Sutcu R, et al. Chlorpyrifos increases the levels of hippocampal NMDA receptor subunits NR2A and NR2B in juvenile and adult rats. Int J Neurosci 2007; 117:47-62.
[41]Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401:63-69.
[42]Wong RW, Setou M, Teng J, Takei Y, Hirokawa N. Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc Natl Acad Sci U S A 2002; 99:14500-14505.
[43]Cao X, Cui Z, Feng R, et al. Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur J Neurosci 2007; 25:1815-1822.
[44] Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci 2004; 5:771-781.
[45]Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A 2007; 104:13501-13506.
Austin, J. K. and Dunn, D. W., 2002. Progressive behavioral changes in children with epilepsy. Prog Brain Res. 135,419-427.
Bannerman, D. M., Deacon, R.M., Offen, S., Friswell, J., Grubb, M. and Rawlins, J. N., 2002. Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behav Neurosci. 116, 884-901.
Bennett, J. C., McRae, P. A., Levy, L. J. and Frick, K. M., 2006. Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice. Neurobiol Learn Mem. 85,139-152.
Bliss, T. V. and Collingridge, G. L., 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 361, 31-39.
Bolanos, A. R., Sarkisian, M., Yang, Y., Hori, A., Helmers, S. L., Mikati, M., Tandon, P., Stafstrom, C. E. and Holmes, G. L., 1998. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology. 51,41-48.
Calabrese, B., Shaked, G. M., Tabarean, I. V., Braga, J., Koo, E. H. and Halpain, S., 2007. Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Mol Cell Neurosci. 35,183-193.
Calhoun, M. E., Kurth, D., Phinney, A. L., Long, J. M., Hengemihle, J., Mouton, P. R., Ingram, D. K. and Jucker, M., 1998. Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice. Neurobiol Aging. 19, 599-606.
Chang, Y. C., Huang, A. M., Kuo, Y. M., Wang, S. T., Chang, Y. Y. and Huang, C. C., 2003. Febrile seizures impair memory and cAMP response-element binding protein activation. Ann Neurol. 54, 706-718.
Chen, G. H., Wang, Y. J., Qin, S., Yang, Q. G., Zhou, J. N. and Liu, R. Y, 2007. Age-related spatial cognitive impairment is correlated with increase of synaptotagmin 1 in dorsal hippocampus in SAMP8 mice. Neurobiol Aging. 28, 611-618.
Chen, L. S., Wong, J. G., Banerjee, P. K. and Snead, O. C., 3rd, 1996. Kainic acid-induced focal cortical seizure is associated with an increase of synaptophysin immunoreactivity in the cortex. Exp Neurol. 141,25-31.
Cheung, M. C., Chan, A. S., Chan, Y. L., Lam, J. M. and Lam, W., 2006. Effects of illness duration on memory processing of patients with temporal lobe epilepsy. Epilepsia. 47,1320-1328.
Costantin, L., Bozzi, Y., Richichi, C., Viegi, A., Antonucci, F., Funicello, M., Gobbi, M., Mennini, T., Rossetto, O., Montecucco, C., Maffei, L., Vezzani, A. and Caleo, M., 2005. Antiepileptic effects of botulinum neurotoxin E. J Neurosci. 25,1943-1951.
Dickson, J.M., Wilkinson, I. D., Howell, S. J., Griffiths, P. D. and Grunewald, R. A., 2006. Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy. J Neurol Neurosurg Psychiatry. 77, 834-840.
Engert, F. and Bonhoeffer, T., 1999. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 399, 66-70.
Fernandez-Chacon, R., Konigstorfer, A., Gerber, S. H., Garcia, J., Matos, M. F., Stevens, C. F., Brose, N., Rizo, J., Rosenmund, C. and Sudhof, T. C., 2001. Synaptotagmin I functions as a calcium regulator of release probability. Nature. 410,41-49.
File, S. E., 1993. The interplay of learning and anxiety in the elevated plus-maze. Behav Brain Res. 58,199-202.
Frankland, P. W. and Bontempi, B., 2005. The organization of recent and remote memories. Nat Rev Neurosci. 6,119-130.
Frassoni, C., Inverardi, F., Coco, S., Ortino, B., Grumelli, C., Pozzi, D., Verderio, C. and Matteoli, M., 2005. Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience. 131, 813-823.
Fuentes-Santamaria, V., Alvarado, J. C., Henkel, C. K. and Brunso-Bechtold, J. K., 2007. Cochlear ablation in adult ferrets results in changes in insulin-like growth factor-1 and synaptophysin immunostaining in the cochlear nucleus. Neuroscience. 148, 1033-1047.
Gerst, J. E., 2003. SNARE regulators: matchmakers and matchbreakers. Biochim Biophys Acta. 1641,99-110.
Gosso, M. F., de Geus, E. J., van Belzen, M. J., Polderman, T. J., Heutink, P., Boomsma, D. I. and Posthuma, D., 2006. The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts. Mol Psychiatry. 11,878-886.
Haas, K. Z., Sperber, E. F., Opanashuk, L. A., Stanton, P. K. and Moshe, S. L., 2001. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus. 11,615-625.
Hanaya, R., Boehm, N. and Nehlig, A., 2007. Dissociation of the immunoreactivity of synaptophysin and GAP-43 during the acute and latent phases of the lithium-pilocarpine model in the immature and adult rat. Exp Neurol. 204, 720-732.
Haut, S. R., Veliskova, J. and Moshe, S. L., 2004. Susceptibility of immature and adult brains to seizure effects. Lancet Neurol. 3,608-617.
Hermann, B. P., Seidenberg, M., Dow, C., Jones, J., Rutecki, P., Bhattacharya, A. and Bell, B., 2006. Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol. 60, 80-87.
Hinz, B., Becher, A., Mitter, D., Schulze, K., Heinemann, U., Draguhn, A. and Ahnert-Hilger, G., 2001. Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain. Eur J Cell Biol. 80, 615-619.
Hodel, A., 1998. Snap-25. Int J Biochem Cell Biol. 30,1069-1073.
Hou, Q., Gao, X., Zhang, X., Kong, L., Wang, X., Bian, W., Tu, Y., Jin,M., Zhao, G., Li, B., Jing, N. and Yu, L., 2004. SNAP-25 in hippocampal CA1 region is involved in memory consolidation. Eur J Neurosci. 20,1593-1603.
Hou, Q. L., Gao, X., Lu, Q., Zhang, X. H., Tu, Y. Y., Jin, M. L., Zhao, G. P., Yu, L., Jing, N. H. and Li, B. M., 2006. SNAP-25 in hippocampal CA3 region is required for long-term memory formation. Biochem Biophys Res Commun. 347, 955-962.
Jiang, Q., Wang, J., Wu, X. and Jiang, Y., 2007. Alterations of NR2B and PSD-95 expression after early-life epileptiform discharges in developing neurons. Int J Dev Neurosci. 25,165-170.
Koh, T. W. and Bellen, H. J., 2003. Synaptotagmin I, a Ca2+ sensor for neurotransmitter release. Trends Neurosci. 26,413-422.
Lee, C. L., Hannay, J., Hrachovy, R., Rashid, S., Antalffy, B. and Swann, J. W., 2001. Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience. 107,71-84.
Liu, F. Y., Wang, X. F., Li, M. W., Li, J. M., Xi, Z. Q., Luan, G. M., Zhang, J. G., Wang, Y. P., Sun, J. J. and Li, Y. L., 2007. Upregulated expression of postsynaptic density-93 and N-methyl-D-aspartate receptors subunits 2B mRNA in temporal lobe tissue of epilepsy. Biochem Biophys Res Commun. 358, 825-830.
Looney, M. R., Dohan, F. C., Jr., Davies, K. G., Seidenberg, M., Hermann, B. P. and Schweitzer, J. B., 1999. Synaptophysin immunoreactivity in temporal lobe epilepsy-associated hippocampal sclerosis. Acta Neuropathol. 98,179-185.
Loscher, W., 2002. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res. 50,105-123.
Martin, S. J., Grimwood, P. D. and Morris, R. G., 2000. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci. 23,649-711.
McHugh, S. B., Deacon, R. M., Rawlins, J. N. and Bannerman, D. M., 2004. Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behav Neurosci. 118,63-78.
Morris, R., 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 11,47-60.
Niikura, Y., Abe, K. and Misawa, M., 2004. Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats. Brain Res. 1017,218-221.
Pauli, E., Hildebrandt, M., Romstock, J., Stefan, H. and Blumcke, I., 2006. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology. 67, 1383-1389.
Prut, L. and Belzung, C., 2003. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol. 463, 3-33.
Racine, R., Okujava, V. and Chipashvili, S., 1972. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol. 32, 295-299.
Reddy, P. H., Mani, G., Park, B. S., Jacques, J., Murdoch, G., Whetsell, W., Jr., Kaye, J. and Manczak, M., 2005. Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alzheimers Dis. 7, 103-117; discussion 173-180.
Roberts, L. A., Morris, B. J. and O'Shaughnessy, C. T., 1998. Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus. Neuroreport. 9, 33-36.
Sayin, U., Sutula, T. P. and Stafstrom, C. E., 2004. Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia. 45,1539-1548.
Selkoe, D. J., 2002. Alzheimer's disease is a synaptic failure. Science. 298, 789-791.
Smith, T. D., Adams, M. M., Gallagher, M., Morrison, J. H. and Rapp, P. R., 2000. Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci. 20, 6587-6593.
Spellmann, I., Muller, N., Musil, R., Zill, P., Douhet, A., Dehning, S., Cerovecki, A., Bondy, B., Moller, H. J. and Riedel, M., 2008. Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci. 258, 335-344.
Stables, J. P., Bertram, E. H., White, H. S., Coulter, D. A., Dichter, M. A., Jacobs, M. P., Loscher, W., Lowenstein, D. H., Moshe, S. L., Noebels, J. L. and Davis, M., 2002. Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia. 43,1410-1420.
Su, H., Sochivko, D., Becker, A., Chen, J., Jiang, Y., Yaari, Y. and Beck, H., 2002. Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus. J Neurosci. 22, 3645-3655.
Sudhof, T. C., 2002. Synaptotagmins: why so many? J Biol Chem. 277, 7629-7632.
Suh, E. C., Jung, Y. J., Kim, Y. A., Park, E. M. and Lee, K. E., 2008. A beta 25-35 induces presynaptic changes in organotypic hippocampal slice cultures. Neurotoxicology. 29, 691-699.
Sutula, T., Lauersdorf, S., Lynch, M., Jurgella, C. and Woodard, A., 1995. Deficits in radial arm maze performance in kindled rats: evidence for long-lasting memory dysfunction induced by repeated brief seizures. J Neurosci. 15, 8295-8301.
Sze, C. I., Troncoso, J. C., Kawas, C., Mouton, P., Price, D. L. and Martin, L. J., 1997. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol. 56, 933-944.
Tocco, G., Bi, X., Vician, L., Lim, I. K., Herschman, H. and Baudry, M., 1996. Two synaptotagmin genes, Sytl and Syt4, are differentially regulated in adult brain and during postnatal development following kainic acid-induced seizures. Brain Res Mol Brain Res. 40,229-239.
Ullrich, B., Li, C., Zhang, J. Z., McMahon, H., Anderson, R. G., Geppert, M. and Sudhof, T. C., 1994. Functional properties of multiple synaptotagmins in brain. Neuron. 13, 1281-1291.
Veinbergs, I., Mante, M., Jung, M. W., Van Uden, E. and Masliah, E., 1999. Synaptotagmin and synaptic transmission alterations in apolipoprotein E-deficient mice. Prog Neuropsychopharmacol Biol Psychiatry. 23, 519-531.
Xiao, Z., Gong, Y., Wang, X. F., Xiao, F., Xi, Z. Q., Lu, Y. and Sun, H. B., 2008. Altered Expression of Synaptotagmin I In Temporal Lobe Tissue of Patients With Refractory Epilepsy.J Mol Neurosci.
Yang,J.W.,Czech,T.,Felizardo,M.,Baumgartner,C.and Lubec,G.,2006.Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy.Amino Acids.30,477-493.
Yin,S.,Guan,Z.,Tang,Y.,Zhao,J.,Hong,J.and Zhang,W.,2005.Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid.Brain Res.1053,195-202.
Zeng,K.,Wang,X.,Wang,Y.and Yan,Y.,2008.Enhanced Synaptic Vesicle Traffic in Hippocampus of Phenytoin-Resistant Kindled Rats.Neurochem Res.
Zhang,Y.,Vilaythong,A.P.,Yoshor,D.and Noebels,J.L.,2004.Elevated thalamic low-voltage-activated currents precede the onset of absence epilepsy in the SNAP25-deficient mouse mutant coloboma.J Neurosci.24,5239-5248.
Zhou,J.L.,Shatskikh,T.N.,Liu,X.and Holmes,G.L.,2007.Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures.Eur J Neurosci.25,3667-3677.