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

氨基酸，L-谷氨酸和GABA作为主要的兴奋性和抑制性神经递质，分别在人脑。这些氨基酸在神经元和神经胶质细胞中的高亲和力转运体对于从突触间隙中去除这些递质和调节其细胞外浓度是必不可少的。有令人信服的证据表明，癫痫与多巴胺能和GAB能神经传递平衡的变化有关。最近，有人提出，GABA和谷氨酸转运蛋白的变化可能是重要的癫痫发生和癫痫发作传播。在这篇文章中，我们专注于参与谷氨酸转运体在癫痫。一种广泛分布的星形胶质细胞谷氨酸转运体，缺乏的纯合子小鼠表现出致命的自发性癫痫发作，其行为模式与NMDA诱导的癫痫发作相似，其特征是爆炸性奔跑，随后保持角弓反张和斯特劳布尾巴，并增加对PTZ诱导的癫痫发作的敏感性。尽管在GLAST、EAAC 1和EAAT 4缺陷小鼠中未观察到自发性癫痫发作，但GLAST缺陷小鼠显示杏仁核点燃癫痫发作的全身性癫痫发作持续时间延长，并且对PTZ诱导的癫痫发作的敏感性增加。这些结果表明，神经胶质细胞谷氨酸转运蛋白比神经元谷氨酸转运蛋白对癫痫发生和癫痫传播的贡献更大。胶质细胞谷氨酸转运体可能成为癫痫治疗的新靶点。

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.