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Functional relationship between neuron and glia in glutamatergic synapses

谷氨酸能突触中神经元和胶质细胞之间的功能关系

基本信息

批准号：
14208096
负责人：
OZAWA Seiji
金额：
$ 32.36万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

In this study, we aimed to clarify the functional relationship between neuron and glia in glutamatergic synapses in the cerebellum and hippocampus. The main results are as follows :1.Roles of glutamate transporters in cerebellar Purkinje cell (PC) synapses.Four distinct glutamate transporters, GLAST, GLT-1, EAAC1 and EAAT4, are distributed near excitatory synapses in cerebellar PCs. GLAST and GLT-1 are expressed in Bergmann glia (BG) wrapping excitatory synapses on PCs, whereas EAAC1 and EAAT4 are expressed in Purkinje cells. Using mutant mice deficient in these transporter genes, we have shown that GLAST and GLT-1 contribute mainly to uptake of glutamate that floods out of the synaptic cleft at early times after transmitter release. In contrast, the main role of EAAT4 is to remove low concentrations of glutamate that escape from the uptake by glial transporters at late times and thus to prevent the transmitter from spilling over to neighboring synapses. The contribution of EAAC1 was n … More egligible. We have also shown that glial glutamate transporters (GLAST plus GLT-1) are expressed in surplus around PC excitatory synapses, and that only 20% of them are needed to retain the fast kinetics of EPSCs.2.Roles of glial glutamate transporters in hippocampal pyramidal cell synapses.Using a novel glutamate transporter blocker (TFB-TBOA) that specifically suppresses glial glutamate transporters, we have shown that the continuous uptake of synaptically released glutamate is indispensable for protecting hippocampal pyramidal neurons from NMDA receptor-mediated hyper-excitabilities. This suggests that dysfunction of glial glutamate transporters is involved in the genesis of epilepsy.3.Regulation of the morphology of glial processes by Ca^<2+>-permeable AMPA receptors.Using a human glioma cell line U-87 MG cells expressing AMPA receptors as a model system, we have shown that the extension of cellular processes of glial cells is regulated by manipulating expression of Ca^<2+>-permeable AMPA receptors. Less

本研究旨在阐明小脑和海马神经元和胶质细胞在突触中的功能关系。主要结果如下：1.谷氨酸转运体在小脑浦肯野细胞突触中的作用：在小脑浦肯野细胞的兴奋性突触附近分布着四种不同的谷氨酸转运体GLAST、GLT-1、EAAC 1和EAAT 4。GLAST和GLT-1在包裹PC上的兴奋性突触的Bergmann神经胶质（BG）中表达，而EAAC 1和EAAT 4在浦肯野细胞中表达。使用这些转运蛋白基因缺陷的突变小鼠，我们已经表明，GLAST和GLT-1主要有助于谷氨酸的摄取，谷氨酸在递质释放后的早期从突触间隙流出。相比之下，EAAT 4的主要作用是去除低浓度的谷氨酸，这些谷氨酸在晚期从神经胶质转运蛋白的摄取中逃逸，从而防止递质溢出到邻近的突触。EAAC 1的贡献率为n ...更多信息可圈可点我们还发现神经胶质谷氨酸转运蛋白结果表明，在PC兴奋性突触周围，GLAST + GLT-1的表达量过剩，且仅需20%的GLAST + GLT-1就能维持EPSC的快速动力学。2.胶质细胞谷氨酸转运体在海马锥体细胞突触中的作用（TFB-TBOA）特异性抑制神经胶质谷氨酸转运蛋白，我们已经表明，突触释放的谷氨酸的持续摄取对于保护海马锥体神经元免受NMDA受体的伤害是必不可少的，介导的过度兴奋。3. Ca^<2+>-可渗透AMPA受体对胶质细胞突起形态的调控以表达AMPA受体的人胶质瘤细胞系U-87 MG细胞为模型系统，我们发现，通过调控Ca^<2+>-可渗透AMPA受体的表达，可以调控胶质细胞突起的延伸。少