Decreased susceptibility to seizures induced by pentylenetetrazole in serine racemase knockout mice

作者：Harai Tomomi; Inoue Ran; Fujita Yuko; Tanaka Ayumi; Horio Mao; Hashimoto Kenji; Hongou Kazuhisa; Miyawaki Toshio; Mori Hisashi^*

来源：Epilepsy Research, 2012, 102(3): 180-187.

DOI：10.1016/j.eplepsyres.2012.06.001

• Serine racemase
• D-Serine
• NMDA receptor
• Clonic-tonic seizure
• c-Fos
• Glutamate

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.

• 出版日期2012-12