rTg4510转基因小鼠海马CA1区突触可塑性的研究
摘要
随着全世界老龄化的日渐加剧,越来越多的人将受到阿尔茨海默氏症(早老性痴呆症)的折磨。其主要表现为神经元的退行性病变所引起的痴呆症状。发病机制还不完全清楚,并且还没有找到有效的治疗方法。rTg4510转基因小鼠模型淀粉样斑块和神经元纤维缠结的形成所导致的神经元的退行性病变和行为学损害等方面都与AD患者有很多相似之处,为研究AD的理想动物模型。海马是参与学习记忆的大脑重要脑区,使其成为研究以学习记忆损伤为主要特征的AD的重要靶点。本课题主要从形态学、电生理学角度证明了此模型在仅仅过度表达人类突变Tau,而没有出现NFT形成之前(1.3M),海马CA1区突触可塑性没有明显的改变。但是在NFT前体物质及NFT出现以后,明显的细胞变性死亡之前(4.5M),已经出现了海马CA1区诱导长时程增强的损伤。
Now more and more people are suffering from Alzheimer's disease (AD) ,when the whole world enter in a aging period. According to the United Nation’s Reporting, Alzheimer's disease are related with 60% of the aging population. There were 25 million AD patients in 2000.The patients number will reach 63 million in 2030,.and it will increase to 114 million by 2050. At present, only the United States spent nearly 90 billion U.S. dollars annually on Alzheimer's disease, including diagnosis, treatment and patient daily caring. The main clinical manifestations of AD are learning and memory impairment and cognitive dysfunction which caused by neuronal degeneration, This disease severely affect the daily lives quality of the elderly. There are a lot of risk factors which be already reported, such as family genetic factors , the level of education, There is a lot of risk factors on its incidence reports, genetic factors such as family, culture, education level, traumatic brain injury, female menopause estrogen declining. but its pathogenetic mechanisum is not entirely clear, and there are many method and medicine for treatment of AD, but there is no reliable and effective treatment now. So AD researching has already become a current hot area of neurological and neurobiological researching. Senile plaques and neurofibrillary tangles were considered two major AD pathological characters . At the same time AD will show the deficits of network activities, which cause the Dysfunction of neuron and cell degeneration finally.
Intracellular neurofibrillary tangles (NFT) is a very important pathological character of AD. Its basic structure is the double-helical filament (PHF). A small amoumt of NFT is a common phenomenon in the elderly brain, but in AD patients brain, Intracellular the quantity and distribution of NFT significantly increased. So the many researcher think NFT is the main mechanism of neuron degeneration in AD. Tau protein, a widely distributed microtubule-associated proteins,is located in axonal and neuronal cell bodies, There are multiple phosphorylation sites on it. Its main function is to bind the ,promote tubulin polymerization and the maintenance of microtubule stability. AD patient’s brain, hyperphosphorylation of Tau reduces the possibility of the combination of tubulin. Currently phosphorylation of Tau in cerebrospinal fluid has become a recognized biological marker of AD.
According to current study, It’s hard to build a animal model which can entirely mimic human neuropathology and dementia symptoms of AD. They Can only achieve similar significant loss of learning and memory ability and cognitive deficits, such as lesion of bilateral sensory-motor cortex, injection of excitatory amino acids in cerebral basal nucleus, etc., but they should not appear typical pathological features (senile plaques and NFT ) in AD brain. And AD transgenic animal model’s building has made significant progress in the human AD research (it was called one of the top ten achievements in human diseases researching in the past 20 years). Currently the following gene were considered as AD pathogenesis-related gene: APP gene, PS1 gene, PS2 gene, ApoE gene and gene encoding Tau, while the most frequent application of AD transgenic model are: APP transgenic model, PS1 transgenic model, Tau transgenic model and simultaneously Expression of the three human mutant gene 3xTg-AD model. Until recently rTg4510 transgenic model of AD led to a lots of attentions from researchers, rTg4510 model is a dual-transgenic model, To express tau, this tau responder gene must be co-expressed with an activator transgene consisting of the tet-off open reading frame which is downstream of Ca2-calmodulin kinase II promoter elements, resulting in P301L tau expression restricted to forebrain structures.And the frontal cortex and hippocampus are closely related to learning and memory and cognitive function,so rTg4510 tran- sgenic model can specifically mimic NFT formation, cognitive function and substantial damage to neurons degeneration of death forebrain in forebrain in AD. Therefore the study of this model has an important significance to study memory impairment and cognitive dysfunction of AD.
Hippocampus is the one of most fragile area according to brain injury of aging process. Hippocampal dentate gyrus’s (dentate gyrus) spine intensity significantly decreased in outside half and inside half of the molecular layer in AD patients brain. Tau pathology study of hippocampal CA1 area in rTg4510 mouse model shows: production of precursors HFT-like substance starting in 2.5 months (2.5M) old transgenic mice, formation of mature NFT around 3M, degeneration of CA1 neurons began around 5.5 M, a large number of neuron death around 9M. 10M of Tg + / + mice show far less brain size than the control mice. In the study of Morris water maze behavior test, 1.3MTg+/+ mice showed no spatial learning and memory deficits, but 2.5M-4M mice start showing o spatial learning and memory deficits. Hippocampal synaptic plasticity researching was widely set up, and long-term potentiation (LTP) was characterized by long term and united, so many researchers linked LTP with learning and memory, and think its probably are neural basis of learning and memory.
My project apply hippocampal CA1 neurons, dendrites and dendritic spine morphology analysis, whole-cell patch clamp recording and hippocampal field recording technique, from the perspective of morphology and electrophysiology research,to analysis the change of synaptic plasticity of hippocampal CA1 area in rTg4510 transgenic mice before it shows the apparent degeneration of neurons.
(1)Brain weight measurement results showed: There was no significant difference (P> 0.05) whole brain weight and brain weight between 1.3M control mice and 1.3M Tg + / + mice. There was no significant difference (P> 0.05) whole brain weight and brain weight between 4.5M control mice and 4.5M Tg + / + mice.And 4.5M mice brain/ body weight ratio showed no difference within control and Tg + / + group(P> 0.05).
(2)Morphological result showed: Hippocampal CA1 pyramidal neurons biotin staining showed that the soma size, dendritic trunk length, direction and distribution of dendrite were similar comparing control group and Tg + / + group in 1.3M and 4.5M mice. Golgi staining results showed that there is no significant difference of soma size within two groups in 4.5M mice (P > 0.05); there is no significant difference of basal dendritic complexity within two groups in 4.5M mice (P > 0.05); there is no significant difference of basal dendrite sipne number between the control group with Tg + / + group in 4.5M mice (P > 0.05); but the number of apical dendritic spines of Tg + / + group significantly decreased compared with control group (P <0.05).
(3)Basic electrophysiological characteristics results of hippocampal CA1 pyramidal neurons showed that:①resting membrane potential: there is no significant difference of resting membrane potential value between the control group with Tg + / + group in 1.3M and 4.5M mice (P > 0.05).②Action potential threshold: there is no significant difference of threshold value between the control group with Tg + / + group in 1.3M and 4.5M mice (P > 0.05).③Input Resistance: there is no significant difference of Rn value between the control group with Tg + / + group in 1.3M and 4.5M mice (P > 0.05).
( 4 ) Spontaneous postsynaptic currents results showed,①spontaneous excitatory postsynaptic current (sEPSC): In 1.3M mice, there are no significant difference of amplitude and decay time of sEPSC between the control group with Tg + / + group (P> 0.05), while frequency of sEPSC in Tg + / + group was significantly higher than control group (P <0.001); In 4.5M mice, there are no significant difference of frequency and decay time of sEPSC between the control group with Tg + / + group (P> 0.05),while amplitude of sEPSC in Tg + / + group was significantly lower than control group (P <0.05).②spontaneous inhibitory postsynaptic current (sIPSC): In 1.3M mice, there are no significant difference of amplitude and frequency of sIPSC between the control group with Tg + / + group (P> 0.05), while decay time of sIPSC in Tg + / + group was significantly lower than control group (P <0.05). In 4.5M mice, there are no significant difference of amplitude and decay time of sIPSC between the control group with Tg + / + group (P> 0.05),while frequency of sIPSC in Tg + / + group was significantly higher than control group (P <0.05).
(5)synaptic plasticity results of whole-cell recording showed,①PPF: In 1.3M mice, there are no difference of paired pulse ratio in different stimulus intervals between the control group with Tg + / + group (P> 0.05) ; In 4.5M mice, there are also no difference of paired pulse ratio in different stimulus intervals between the control group with Tg + / + group (P> 0.05).②LTP: there are no significant diference of LTP amplitude which induced by TBS between the control group with Tg + / + group in 1.3M and 4.5M mice (P> 0.05).
(6)synaptic plasticity results of field recording showed,①PPF: In 1.3M mice, there are no difference of in different stimulus intervals between the control group with Tg + / + group (P> 0.05) ;;while In 4.5M mice, paired pulse ratio of Tg + / + group was significantly higher than control group in all stimulus intervals (P <0.05).②LTP: In 1.3M mice, there are no significant diference of LTP amplitude which induced by 1×TBS between the control group with Tg + / + group (P> 0.05); but In 4.5M mice, 1×TBS induced LTP amplitude in Tg + / + was significantly lower than the control group (P <0.05).
We can draw the following conclusion from the above results:
1. neurons morphology results showed that :There are no apparent neuron degeneration of hippocampal CA1 area in 1.3M and 4.5M Tg + / + mice.
2. Spontaneous postsynaptic current results show that: excitatory postsynaptic network activity of CA1 neuron increased in 1.3M Tg + / + mice, and inhibitory postsynaptic network activity of CA1 neuron increased in 4.5M Tg + / + mice.
3. synaptic plasticity results of whole cell recording and field recording showed: before hippocampal CA1 area does not appear obvious neuronal degeneration, 4.5M Tg+/+ mice have already showed the deficits of LTP induction. And this kind of change was due to the deficits of . LTP induction of population neurons but not the single neuron.
Now more and more people are suffering from Alzheimer's disease (AD) ,when the whole world enter in a aging period. According to the United Nation’s Reporting, Alzheimer's disease are related with 60% of the aging population. There were 25 million AD patients in 2000.The patients number will reach 63 million in 2030,.and it will increase to 114 million by 2050. At present, only the United States spent nearly 90 billion U.S. dollars annually on Alzheimer's disease, including diagnosis, treatment and patient daily caring. The main clinical manifestations of AD are learning and memory impairment and cognitive dysfunction which caused by neuronal degeneration, This disease severely affect the daily lives quality of the elderly. There are a lot of risk factors which be already reported, such as family genetic factors , the level of education, There is a lot of risk factors on its incidence reports, genetic factors such as family, culture, education level, traumatic brain injury, female menopause estrogen declining. but its pathogenetic mechanisum is not entirely clear, and there are many method and medicine for treatment of AD, but there is no reliable and effective treatment now. So AD researching has already become a current hot area of neurological and neurobiological researching. Senile plaques and neurofibrillary tangles were considered two major AD pathological characters . At the same time AD will show the deficits of network activities, which cause the Dysfunction of neuron and cell degeneration finally.
Intracellular neurofibrillary tangles (NFT) is a very important pathological character of AD. Its basic structure is the double-helical filament (PHF). A small amoumt of NFT is a common phenomenon in the elderly brain, but in AD patients brain, Intracellular the quantity and distribution of NFT significantly increased. So the many researcher think NFT is the main mechanism of neuron degeneration in AD. Tau protein, a widely distributed microtubule-associated proteins,is located in axonal and neuronal cell bodies, There are multiple phosphorylation sites on it. Its main function is to bind the ,promote tubulin polymerization and the maintenance of microtubule stability. AD patient’s brain, hyperphosphorylation of Tau reduces the possibility of the combination of tubulin. Currently phosphorylation of Tau in cerebrospinal fluid has become a recognized biological marker of AD.
According to current study, It’s hard to build a animal model which can entirely mimic human neuropathology and dementia symptoms of AD. They Can only achieve similar significant loss of learning and memory ability and cognitive deficits, such as lesion of bilateral sensory-motor cortex, injection of excitatory amino acids in cerebral basal nucleus, etc., but they should not appear typical pathological features (senile plaques and NFT ) in AD brain. And AD transgenic animal model’s building has made significant progress in the human AD research (it was called one of the top ten achievements in human diseases researching in the past 20 years). Currently the following gene were considered as AD pathogenesis-related gene: APP gene, PS1 gene, PS2 gene, ApoE gene and gene encoding Tau, while the most frequent application of AD transgenic model are: APP transgenic model, PS1 transgenic model, Tau transgenic model and simultaneously Expression of the three human mutant gene 3xTg-AD model. Until recently rTg4510 transgenic model of AD led to a lots of attentions from researchers, rTg4510 model is a dual-transgenic model, To express tau, this tau responder gene must be co-expressed with an activator transgene consisting of the tet-off open reading frame which is downstream of Ca2-calmodulin kinase II promoter elements, resulting in P301L tau expression restricted to forebrain structures.And the frontal cortex and hippocampus are closely related to learning and memory and cognitive function,so rTg4510 tran- sgenic model can specifically mimic NFT formation, cognitive function and substantial damage to neurons degeneration of death forebrain in forebrain in AD. Therefore the study of this model has an important significance to study memory impairment and cognitive dysfunction of AD.
Hippocampus is the one of most fragile area according to brain injury of aging process. Hippocampal dentate gyrus’s (dentate gyrus) spine intensity significantly decreased in outside half and inside half of the molecular layer in AD patients brain. Tau pathology study of hippocampal CA1 area in rTg4510 mouse model shows: production of precursors HFT-like substance starting in 2.5 months (2.5M) old transgenic mice, formation of mature NFT around 3M, degeneration of CA1 neurons began around 5.5 M, a large number of neuron death around 9M. 10M of Tg + / + mice show far less brain size than the control mice. In the study of Morris water maze behavior test, 1.3MTg+/+ mice showed no spatial learning and memory deficits, but 2.5M-4M mice start showing o spatial learning and memory deficits. Hippocampal synaptic plasticity researching was widely set up, and long-term potentiation (LTP) was characterized by long term and united, so many researchers linked LTP with learning and memory, and think its probably are neural basis of learning and memory.
My project apply hippocampal CA1 neurons, dendrites and dendritic spine morphology analysis, whole-cell patch clamp recording and hippocampal field recording technique, from the perspective of morphology and electrophysiology research,to analysis the change of synaptic plasticity of hippocampal CA1 area in rTg4510 transgenic mice before it shows the apparent degeneration of neurons.
(1)Brain weight measurement results showed: There was no significant difference (P> 0.05) whole brain weight and brain weight between 1.3M control mice and 1.3M Tg + / + mice. There was no significant difference (P> 0.05) whole brain weight and brain weight between 4.5M control mice and 4.5M Tg + / + mice.And 4.5M mice brain/ body weight ratio showed no difference within control and Tg + / + group(P> 0.05).
(2)Morphological result showed: Hippocampal CA1 pyramidal neurons biotin staining showed that the soma size, dendritic trunk length, direction and distribution of dendrite were similar comparing control group and Tg + / + group in 1.3M and 4.5M mice. Golgi staining results showed that there is no significant difference of soma size within two groups in 4.5M mice (P > 0.05); there is no significant difference of basal dendritic complexity within two groups in 4.5M mice (P > 0.05); there is no significant difference of basal dendrite sipne number between the control group with Tg + / + group in 4.5M mice (P > 0.05); but the number of apical dendritic spines of Tg + / + group significantly decreased compared with control group (P <0.05).
(3)Basic electrophysiological characteristics results of hippocampal CA1 pyramidal neurons showed that:①resting membrane potential: there is no significant difference of resting membrane potential value between the control group with Tg + / + group in 1.3M and 4.5M mice (P > 0.05).②Action potential threshold: there is no significant difference of threshold value between the control group with Tg + / + group in 1.3M and 4.5M mice (P > 0.05).③Input Resistance: there is no significant difference of Rn value between the control group with Tg + / + group in 1.3M and 4.5M mice (P > 0.05).
( 4 ) Spontaneous postsynaptic currents results showed,①spontaneous excitatory postsynaptic current (sEPSC): In 1.3M mice, there are no significant difference of amplitude and decay time of sEPSC between the control group with Tg + / + group (P> 0.05), while frequency of sEPSC in Tg + / + group was significantly higher than control group (P <0.001); In 4.5M mice, there are no significant difference of frequency and decay time of sEPSC between the control group with Tg + / + group (P> 0.05),while amplitude of sEPSC in Tg + / + group was significantly lower than control group (P <0.05).②spontaneous inhibitory postsynaptic current (sIPSC): In 1.3M mice, there are no significant difference of amplitude and frequency of sIPSC between the control group with Tg + / + group (P> 0.05), while decay time of sIPSC in Tg + / + group was significantly lower than control group (P <0.05). In 4.5M mice, there are no significant difference of amplitude and decay time of sIPSC between the control group with Tg + / + group (P> 0.05),while frequency of sIPSC in Tg + / + group was significantly higher than control group (P <0.05).
(5)synaptic plasticity results of whole-cell recording showed,①PPF: In 1.3M mice, there are no difference of paired pulse ratio in different stimulus intervals between the control group with Tg + / + group (P> 0.05) ; In 4.5M mice, there are also no difference of paired pulse ratio in different stimulus intervals between the control group with Tg + / + group (P> 0.05).②LTP: there are no significant diference of LTP amplitude which induced by TBS between the control group with Tg + / + group in 1.3M and 4.5M mice (P> 0.05).
(6)synaptic plasticity results of field recording showed,①PPF: In 1.3M mice, there are no difference of in different stimulus intervals between the control group with Tg + / + group (P> 0.05) ;;while In 4.5M mice, paired pulse ratio of Tg + / + group was significantly higher than control group in all stimulus intervals (P <0.05).②LTP: In 1.3M mice, there are no significant diference of LTP amplitude which induced by 1×TBS between the control group with Tg + / + group (P> 0.05); but In 4.5M mice, 1×TBS induced LTP amplitude in Tg + / + was significantly lower than the control group (P <0.05).
We can draw the following conclusion from the above results:
1. neurons morphology results showed that :There are no apparent neuron degeneration of hippocampal CA1 area in 1.3M and 4.5M Tg + / + mice.
2. Spontaneous postsynaptic current results show that: excitatory postsynaptic network activity of CA1 neuron increased in 1.3M Tg + / + mice, and inhibitory postsynaptic network activity of CA1 neuron increased in 4.5M Tg + / + mice.
3. synaptic plasticity results of whole cell recording and field recording showed: before hippocampal CA1 area does not appear obvious neuronal degeneration, 4.5M Tg+/+ mice have already showed the deficits of LTP induction. And this kind of change was due to the deficits of . LTP induction of population neurons but not the single neuron.
引文
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