海马CA1区NSF与空间学习记忆障碍关系的实验研究
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摘要
背景和目的
帕金森病(Parkinson’s Disease，PD)与癫痫(Epilepsy)临床表现不同，但均属于神经系统变性性疾病，神经元变性、脱失为其显著的神经病理学特征。发病机制均涉及脑内神经递质、神经肽释放异常。已有报道PD患者伴有认知障碍，主要表现为早期的视觉空间障碍及短时记忆受损等，严重时常合并痴呆。颞叶癫痫在成人癫痫中预后最差，其60～70％发展成难治性癫痫，病人长期甚至终身服药也不能控制其反复出现的癫痫发作，颞叶癫痫并发认知功能障碍比其它类型癫痫高4～12倍，多为痴呆或精神分裂症样特征。中科院上海生化所与我们合作研究在红藻氨酸(Kainic acid，KA)处理后3周出现癫痫反复发作(Spontaneous recurrent seizure，SRS)的Sprague-Dawley(SD)大鼠的海马结构中克隆出癫痫相关基因(Epilepsy related gene，ERG1)基因(GenBank序号AF142097)经同源性比较与中国仓鼠的N-乙基马来酰亚胺敏感融合蛋白(N-ethylmaleimide-sensitive fusion protein，NSF)以及人类的N-乙基马来酰亚胺敏感融合因子(N-ethylmaleimide-sensitive fusion factor，NEM)基因具有高度的同源性。其蛋白表达产物NSF参与神经递质释放过程中突触囊泡的锚定、融合以及突触可塑性的形成。但是NSF与学习记忆障碍关系不清楚。本研究分别采用颞叶癫痫KA大鼠模型和PD的1-甲基-4-苯基-1，2，3，6-四氢吡啶(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine，MPTP)小鼠模型探讨NSF与空间学习记忆障碍的关系；进一步观察用蝎毒耐热蛋白处理对伴有学习记忆损害的MPTP小鼠模型海马CA1区NSF表达的改变及可能的神经肽及脑内神经炎症机制。
方法
本研究给予SD大鼠颈部皮下注射惊厥剂量(10mg／kg，5mg／ml)的KA，诱发急性癫痫发作，KA后连续观察3周，按Racine描述标准筛选癫痫发作敏感并具有反复发作行为特征的SD大鼠。给予C57BL／6小鼠MPTP(20mg／kg，s．c．)连续8天制备MPTP小鼠PD模型，设立为模型组，腹腔注射给予蝎毒耐热蛋白连续8
Background and Objective
Although the clinical syndrome of Parkinson's disease (PD) and epilepsy are different, both of them belong to the neurodegenerative diseases and have the common typical neuropathological characters, which are the large degeneration and loss of the neurons. The pathological mechanisms are related to the abnormal release of neurotransmitters and neuropeptides. There is an increasing recognition of accompanying impairments in cognition in PD patients. These deficits predominantly affect visual-spatial working memory and develop into the idiot severely. In adults, complex partial seizures such as those occur in temporal lobe epilepsy have the poorest prognosis of all types of seizures, with about 60~70% of all patients having intractable seizures, whose main syndrome is that the patients can't control the spontaneous recurrent seizure (SRS) and depend on the antiepileptic drugs all life. Temporal lobe epilepsy accompanied the psychiatric comorbidity 4—12 times higher than the other types of epilepsy, which focused on the idiotic or psychiatric comorbidity. Shanghai Institute of Biochemistry in Chinese Academy of Sciences cooperated with us and identified an epilepsy-related gene named ERG1 (GenBank accession no. AF142097), which is a gene cloned in the hippocampus of the rats with SRS after kainic acid (KA) injection for 3 weeks. Sequence analysis revealed that ERG1, a SRS related gene, has high similarity to N-ethylmaleimide-sensitive fusion protein (NSF) gene. NSF encoded by ERG1/NSF is an ATPase, which plays a key role in vesicular trafficking and involves the fusion of synaptic vesicles with the presynaptic membrane during the release of neurotransmitter. It also regulates the formation of synapses plasticity. However, the relationship between NSF and learning memory is still unclear. In this study, we used
帕金森病(Parkinson’s Disease，PD)与癫痫(Epilepsy)临床表现不同，但均属于神经系统变性性疾病，神经元变性、脱失为其显著的神经病理学特征。发病机制均涉及脑内神经递质、神经肽释放异常。已有报道PD患者伴有认知障碍，主要表现为早期的视觉空间障碍及短时记忆受损等，严重时常合并痴呆。颞叶癫痫在成人癫痫中预后最差，其60～70％发展成难治性癫痫，病人长期甚至终身服药也不能控制其反复出现的癫痫发作，颞叶癫痫并发认知功能障碍比其它类型癫痫高4～12倍，多为痴呆或精神分裂症样特征。中科院上海生化所与我们合作研究在红藻氨酸(Kainic acid，KA)处理后3周出现癫痫反复发作(Spontaneous recurrent seizure，SRS)的Sprague-Dawley(SD)大鼠的海马结构中克隆出癫痫相关基因(Epilepsy related gene，ERG1)基因(GenBank序号AF142097)经同源性比较与中国仓鼠的N-乙基马来酰亚胺敏感融合蛋白(N-ethylmaleimide-sensitive fusion protein，NSF)以及人类的N-乙基马来酰亚胺敏感融合因子(N-ethylmaleimide-sensitive fusion factor，NEM)基因具有高度的同源性。其蛋白表达产物NSF参与神经递质释放过程中突触囊泡的锚定、融合以及突触可塑性的形成。但是NSF与学习记忆障碍关系不清楚。本研究分别采用颞叶癫痫KA大鼠模型和PD的1-甲基-4-苯基-1，2，3，6-四氢吡啶(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine，MPTP)小鼠模型探讨NSF与空间学习记忆障碍的关系；进一步观察用蝎毒耐热蛋白处理对伴有学习记忆损害的MPTP小鼠模型海马CA1区NSF表达的改变及可能的神经肽及脑内神经炎症机制。
方法
本研究给予SD大鼠颈部皮下注射惊厥剂量(10mg／kg，5mg／ml)的KA，诱发急性癫痫发作，KA后连续观察3周，按Racine描述标准筛选癫痫发作敏感并具有反复发作行为特征的SD大鼠。给予C57BL／6小鼠MPTP(20mg／kg，s．c．)连续8天制备MPTP小鼠PD模型，设立为模型组，腹腔注射给予蝎毒耐热蛋白连续8
Background and Objective
Although the clinical syndrome of Parkinson's disease (PD) and epilepsy are different, both of them belong to the neurodegenerative diseases and have the common typical neuropathological characters, which are the large degeneration and loss of the neurons. The pathological mechanisms are related to the abnormal release of neurotransmitters and neuropeptides. There is an increasing recognition of accompanying impairments in cognition in PD patients. These deficits predominantly affect visual-spatial working memory and develop into the idiot severely. In adults, complex partial seizures such as those occur in temporal lobe epilepsy have the poorest prognosis of all types of seizures, with about 60~70% of all patients having intractable seizures, whose main syndrome is that the patients can't control the spontaneous recurrent seizure (SRS) and depend on the antiepileptic drugs all life. Temporal lobe epilepsy accompanied the psychiatric comorbidity 4—12 times higher than the other types of epilepsy, which focused on the idiotic or psychiatric comorbidity. Shanghai Institute of Biochemistry in Chinese Academy of Sciences cooperated with us and identified an epilepsy-related gene named ERG1 (GenBank accession no. AF142097), which is a gene cloned in the hippocampus of the rats with SRS after kainic acid (KA) injection for 3 weeks. Sequence analysis revealed that ERG1, a SRS related gene, has high similarity to N-ethylmaleimide-sensitive fusion protein (NSF) gene. NSF encoded by ERG1/NSF is an ATPase, which plays a key role in vesicular trafficking and involves the fusion of synaptic vesicles with the presynaptic membrane during the release of neurotransmitter. It also regulates the formation of synapses plasticity. However, the relationship between NSF and learning memory is still unclear. In this study, we used
引文
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