| Project/Area Number |
07557242
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Psychiatric science
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| Research Institution | National Institute of Neuroscience, NCNP |
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Principal Investigator |
NISHIKAWA Toru Natl.Inst.Neurosci., Dept.Mental Disorder Res., Director, 神経研究所・疾病研究第3部, 部長 (00198441)
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| Co-Investigator(Kenkyū-buntansha) |
MORITA Takuma Yamanouchi Pharmaceuticals, Dept.Pharmacol., Senior Researcher, 中央研究所・第一創薬研究所, 主任研究員
WADA Keiji Natl.Inst.Neurosci., Dept.Neurochemistry, Director, 神経センター神経研究所・疾病研究第四部, 部長 (70250222)
KOHSAKA Shinichi Natl.Inst.Neurosci., Dept.Neurochemistry, Director, 神経センター神経研究所・代謝研究部, 部長 (50112686)
TAKAHASHI Katunobu Natl.Inst.Neurosci., Dept.Mental Disorder Res., Senior Chief, 神経センター神経研究所・疾病研究第三部, 室長 (40183850)
越谷 和雄 山之内製薬, 中央研究所・第一創薬研究所, 主任研究員
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥3,100,000 (Direct Cost: ¥3,100,000)
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| Keywords | Endogenous D-serine / Mammalian brains / Extracellular release / Uptake / Biosynthesis / Binding sites / Glycine / L-Serine / 内在性D-セリン / グリア細胞 / GABA伝達系 / D-セリン合成 / 哺乳類 / NMDA受容体チャンネル / グリシン開裂酵素 / グリシン代謝 / L-セリン代謝 / 非NMDA受容体D-セリン結合部位 / 細胞外液中への放出 / 取り込み活性 / 結合活性 / 脳内濃度調節 |
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| Research Abstract |
To obtain an insight into physiological and pathophysiological role of endogenous D-serine in higher brain functions, we have investigated the metabolism of D-serine in the rat and human brain tissues. Substantial concentration of D-serine has been detected in the extracellular fluid of the frontal cortex and striatum of the rat by an in vivo microdialysis technique. Neither calcium ion-free condition nor perfusion of tetrodotoxin reduced extracellular D-serine content in the frontal cortex and a depolarization agent, veratrin, caused an increase in the extracellular release of glutamate, but not D-serine. These data suggest that extracellular D-serine could be liberated from glial cells. [3H]D-Serine was found to be taken up into the cortical and cerebellar P2 franction and the C6 glioma cells in a temperature-and sodium-dependent and saturable manner, indicating the presence a transport system for D-serine. In addition to the glycine modulatory site of the NMDA receptor at which D-serine acts as a potent agonist, [3H]D-serine has also been shown to bind to a novel site in the brain tissues. Moreover, we have observed a profound reduction of cortical D-serine contents in the patients with non-ketotic hyperglycinemia lacking activity of glycine cleavage system (GCS) and in the animal treated with an inhibitor of GCS,cysteamine. Systemic administration of a high amount of L-serine produced a marked increase in cortical D-serine concentrations in the infant rats, vice versa. The present findings further support the view that endogenous D-serine may be involved in the synaptic transmission mediated by the NMDA receptor and other unknown receptor sites. The synthesis of D-serine might be closely related to the metabolism of L-serine and glycine.
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