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Molecular and cytobiological study on regulation of synapse

突触调控的分子和细胞生物学研究

基本信息

批准号：
11694295
负责人：
MIYAMOTO Eishichi
金额：
$ 4.42万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

The elucidation of molecular mechanisms of learning and memory is one of the most important and attractive projects in the field of neuroscience in the 21st century. High frequency stimulation of Schaffer collateral/commissural pathway in the slices of the hippocampus can cause long-lasting potentiation of synaptic transmission efficacy in the pyramidal cells of the CA1 area. This effect is called long-term potentiation (LTP), which is a possible model for a molecular mechanism for learning and memory.The present study elucidated the following findings. 1) LTP induction was associated with a significant decrease in protein phosphatase (PP) 2A activity. 2) A 55-kDa protein was phosphorylated during LTP induction. 3) Analysis with the specific antibody to the regulatory subunits of PP2A demonstrated that the 55-kDa protein is the B'α regulatory subunit of PP2A.4) CaM kinase IV and mitogen-activated protein kinase (MAPK) were transiently activated during LTP induction and returned to the original level within 30 min. Especially CaM kinase IV was activated in neuronal nuclei. 5) Activation of both kinases was associated with cyclic AMP-responsive elementbinding protein (CREB) phosphorylation. The use of inhibitors for CaM kinases and MAPK such as KN93 and U0126, respectively, indicated that CaM kinase IV and MAPK are each involved in CREB phosphorylation. Furthermore, c-Fos expression was stimulated 60 min after high frequency-stimulated LTP.The increase in c-Fos expression was inhibited by addition of calmidazolium and U0126.These results suggest that LTP induction is primarily performed by activation of CaM kinase II and its related reactions through Ca^<2+> influx into postsynaptic neurons by activation of NMDA glutamate receptors. Furthermore, LTP maintenance is associated with stimulation of gene expression and protein synthesis which may be necessary for synthesis of synaptic components and formation of new circuits.

阐明学习记忆的分子机制是世纪神经科学领域最重要和最具吸引力的研究课题之一。海马切片中Schaffer侧支/连合通路的高频刺激可引起CA 1区锥体细胞中突触传递功效的持久增强。这种效应被称为长时程增强（LTP），它是学习和记忆的分子机制的一个可能模型。1)LTP诱导与蛋白磷酸酶（PP）2A活性的显着下降。2)在LTP诱导过程中，一个55 kDa的蛋白质被磷酸化。3)4.CaM激酶IV和丝裂原活化蛋白激酶（MAPK）在LTP诱导过程中被瞬时激活，并在30 min内恢复到初始水平，尤其是CaM激酶IV在神经元核中被激活。5)这两种激酶的激活与环腺苷酸反应元件结合蛋白（CREB）磷酸化有关。CaM激酶和MAPK的抑制剂如KN 93和U 0126的使用分别表明CaM激酶IV和MAPK各自参与CREB磷酸化。高频刺激LTP后60 min，c-Fos表达增加，钙咪唑和U 0126可抑制c-Fos表达的增加。提示LTP的诱导主要是通过激活NMDA谷氨酸受体，激活CaM激酶II及其相关反应，使Ca^2+内流进入突触后神经元。此外，LTP的维持与基因表达和蛋白质合成的刺激有关，这可能是合成突触成分和形成新回路所必需的。