Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Epilepsy Res. 2012 Dec;102(3):180-7. doi: 10.1016/j.eplepsyres.2012.06.001. Epub 2012 Jun 27.
The N-methyl-D-aspartate (NMDA)-type glutamate receptor plays a key role in excitatory synaptic transmission. The overactivation of the NMDA receptor has been implicated in the development of epileptic seizures. D-Serine is a coagonist of the NMDA receptor and its biosynthesis is catalyzed by serine racemase (SR). Here, we examined the effect of d-serine deficiency on the seizures induced by a single injection of pentylenetetrazole (PTZ) using SR knockout (KO) mice. We found that, compared with wild-type (WT) mice, SR-KO mice showed the attenuation of seizure expression in terms of a significantly shortened duration of generalized seizures and resistance to generalized clonic-tonic seizures. Consistently, immunohistochemical analysis of c-Fos demonstrated that the numbers of cells expressing c-Fos induced by high-dose PTZ in the cerebral cortex, hippocampal CA1, hippocampal CA3, and the basolateral nucleus of the amygdala in WT mice were significantly higher than those in SR-KO mice. Moreover, PTZ induced an increase in extracellular glutamate level in the dentate gyrus of WT mice at two different time phases. However, such a PTZ-induced increase in glutamate level was completely inhibited in SR-KO mice. The present findings suggest that SR may be a target for the development of new therapeutic strategies for epileptic seizures.
N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体在兴奋性突触传递中发挥关键作用。NMDA 受体的过度激活与癫痫发作的发展有关。D-丝氨酸是 NMDA 受体的共激动剂，其生物合成由丝氨酸 racemase（SR）催化。在这里，我们使用 SR 敲除（KO）小鼠检查了 D-丝氨酸缺乏对单次戊四氮（PTZ）注射诱导的癫痫发作的影响。我们发现，与野生型（WT）小鼠相比，SR-KO 小鼠在全身性癫痫发作的持续时间明显缩短和对全身性强直-阵挛性癫痫发作的抗性方面表现出癫痫发作表达的减弱。一致地，c-Fos 的免疫组织化学分析表明，在 WT 小鼠的大脑皮层、海马 CA1、海马 CA3 和杏仁核基底外侧核中，高剂量 PTZ 诱导的表达 c-Fos 的细胞数量明显高于 SR-KO 小鼠。此外，PTZ 诱导 WT 小鼠齿状回细胞外谷氨酸水平在两个不同时间点增加。然而，这种 PTZ 诱导的谷氨酸水平增加在 SR-KO 小鼠中完全被抑制。本研究结果表明，SR 可能是开发癫痫治疗新策略的靶点。
