Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy
Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy
复制标题
D-丝氨酸上调可能诱导小鼠毛果芸香碱癫痫模型大脑皮层和海马的 GABA 能神经元变性
DOI：
10.1007/s11064-008-9897-0
复制
发表时间：
2009-07-01
影响因子：
4.4
通讯作者：
Chen, Liang-Wei
中科院分区：
文献类型：
--
作者：
Liu, Yong-Hong;Wang, Lian;Chen, Liang-Wei
癫痫是一种严重的神经系统疾病，伴有神经元丢失和自发性反复发作，但其神经化学基础仍不清楚。我们推测，d-丝氨酸，一个新发现的内源性共激动剂N-甲基-d-天冬氨酸（NMDA）受体，可能会引发兴奋性毒性和神经元损伤癫痫。通过使用小鼠毛果芸香碱模型，免疫组织化学，Fluoro-Jade染色和双标记，本研究揭示了上调的d-丝氨酸表达的比例（41%）的神经元在大脑皮层和海马。d-丝氨酸阳性神经元出现于4 h，12-24 h达高峰，3-14 d逐渐下降。此外，大多数d-丝氨酸阳性神经元是GABA能神经元（98%），经历变性死亡（93%），并伴有NMDA受体亚基1磷酸化增强。本研究为在匹罗卡品模型中d-丝氨酸产生的上调可能通过兴奋毒性机制诱导GABA能神经元变性，并可能参与慢性癫痫的早期发病和反复发作提供了新的证据。
Epilepsy is a serious neurological disorder with neuronal loss and spontaneous recurrent seizures, but the neurochemical basis remains largely unclear. We hypothesize that d-serine, a newly identified endogenous co-agonist of N-methyl-d-aspartate (NMDA) receptor, may trigger excitotoxicity and neuronal damage in epileptogenesis. By using a mouse pilocarpine model, immunohistochemistry, Fluoro-Jade staining and double-labeling, the present study revealed up-regulation of d-serine expression in a proportion (41%) of neurons in the cerebral cortex and hippocampus. The d-serine-positive neurons occurred at 4 h, reached peak levels at 12-24 h, and gradually went down at 3-14 days. Moreover, most of d-serine-positive neurons were GABAergic (98%), underwent degenerating death (93%), and were accompanied enhancing phosphorylation of NMDA receptor subunit 1. This study has provided new evidence that up-regulation of d-serine production might induce GABAergic neuronal degeneration through excitotoxic mechanism in the pilocarpine model and may be involved in early pathogenesis and recurrent seizure of chronic epilepsy.