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Analysis of the mechanisms of epilepsy induced by dysfunction of glutamate transporters

谷氨酸转运蛋白功能障碍诱发癫痫的机制分析

基本信息

批准号：
10480221
负责人：
TANAKA Kohichi
金额：
$ 7.94万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10480221/
关键词：
Glutamate transporter synaptic transmission excitotoxicity Plasticity epilepsy knockout mouse てんかん発作

项目摘要

The amino acids, L-glutamate and GABA serve as major excitatory and inhibitory neurotransmitters, respectively, in the manmmalian brain. High-affinity trantsporters for these amino acids in neurons and glial cells are essential for the removal of these transmitters from the synaptic cleft and for regulating their extracellular concentration. There is compelling evidence that epilepsy is associated with changes in the balance of glutamatergic and GAB Aergic neurotransmission. More recently, it has been suggested that changes in GABA and glutamate transporters may be important in epileptogenesis and seizure propagation. In this article, we focus on the involvement of glutamate transporters in epilepsy. Homozygous mice deficient in, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures with behavioral patterns similar to those of NMDA-induced seizures characterized by explosive running followed by maintained opisthotonus and straub tail and increased susceptibility to PTZ-induced seizures. Although spontaneous seizures were not observed in GLAST-, EAAC1-, and EAAT4-deficient mice, GLAST-deficient mice showed the prolongation of the generalized seizure duration of amygdala-kindled seizures and increased susceptibility to PTZ-induced seizures. These results demonstrated that glial glutamate transporters contribute much more than neuronal glutamate transporters to epileptogenesis and seizure propagation. The glial glutamate transporters might be a new target for manipulating epilepsy.

氨基酸L-谷氨酸和γ-氨基丁酸分别作为主要的兴奋性和抑制性神经递质。神经元和神经胶质细胞中这些氨基酸的高亲和力转运体对于将这些递质从突触间隙中移除并调节它们的细胞外浓度是必不可少的。有令人信服的证据表明，癫痫与谷氨酸和GAB能神经传递平衡的改变有关。最近，有人提出，GABA和谷氨酸转运体的变化可能在癫痫的发生和癫痫的传播中起重要作用。在这篇文章中，我们重点讨论谷氨酸转运体在癫痫中的作用。作为一种广泛分布的星形细胞谷氨酸转运体，In基因缺陷纯合子小鼠表现出致死性的自发发作，其行为模式类似于NMDA诱导的癫痫发作，其特征是爆发式奔跑，随后维持反张和Straub尾巴，并增加对PTZ诱导的癫痫发作的易感性。虽然在GLAST、EAAC1和EAAT4缺陷小鼠中没有观察到自发性癫痫发作，但GLAST缺陷小鼠表现出杏仁核点燃癫痫发作的全身性发作持续时间的延长和对PTZ诱导的癫痫发作的易感性增加。这些结果表明，胶质谷氨酸转运体比神经元谷氨酸转运体在癫痫发生和癫痫传播中的作用要大得多。胶质细胞谷氨酸转运体可能成为控制癫痫的新靶点。