title: Decreased susceptibility to seizures induced by pentylenetetrazole in serine racemase knockout mice.
abstract: 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.
authors: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Tomomi
authors: T
authors: Harai
authors: Ran
authors: R
authors: Inoue
authors: Yuko
authors: Y
authors: Fujita
authors: Ayumi
authors: A
authors: Tanaka
authors: Mao
authors: M
authors: Horio
authors: Kenji
authors: K
authors: Hashimoto
authors: Kazuhisa
authors: K
authors: Hongou
authors: Toshio
authors: T
authors: Miyawaki
authors: Hisashi
authors: H
authors: Mori
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D018613:Microscopy, Confocal; D010433:Pentylenetetrazole / Q000633:toxicity*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D019998:Racemases and Epimerases / Q000172:deficiency*; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D018709:Statistics, Nonparametric; D013997:Time Factors; D000099300:Serine Racemase
chemical_list: D000596:Amino Acids; D003292:Convulsants; D018698:Glutamic Acid; D010433:Pentylenetetrazole; D016760:Proto-Oncogene Proteins c-fos; D019998:Racemases and Epimerases; D000099300:Serine Racemase