Origin and regulation of endogenous D-serine in mammalian brain tissues

哺乳动物脑组织内源性D-丝氨酸的起源和调控

• 批准号: 13670987
• 负责人: KUBOTA Tetsuo
• 金额: $ 2.24万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670987/
• 关键词: Endogenous D-serin; N-Methyl-D-aspartate receptor; Quinolinic acid; Medial frontal cortex; Striatum; Primary culture of hippocampus; Anti-D-serine antibody; Schizophrenia; GABA; ドーパミン; 前頭葉皮質

Using an in vivo dialysis technique, we have studied the extracellular contents of endogenous free D-serine in comparison with that of L-serine, glycine and L-glutamate in the brain of the freely moving rat. A high amount of D-serine was detected in the dialysate obtained from the medial prefrontal cortex and striatum, whereas the cerebellar dialysate contained only a trace concentration of the D-amino acid. Intra-medial prefrontal cortex perfusion of a sodium channel activator, veratrine, augmented the extracellular release of glycine and L-glutamate but a slight decrease in that of D-serine in a tetrodotoxin-sensitive manner in the prefrontal area. Moreover, selective destruction of neuronal cell bodies in the medial frontal region by means of local infusion of an excitotoxin quinolinate resulted in a marked reduction of extracellular and tissue levels of D-serine in the infused prefrontal region. These findings suggest that endogenous Dserine might be liberated into the extracellular space from non-neuronal cells or certain exceptional neuronal cells probably by a carrier-mediated process in the mammalian prefrontal cortex . Also, the endogenous D-amino acid has been indicated to be accumulated or synthesized, at least in part, in the neuronal cells.

本文用活体透析技术研究了自由活动大鼠脑内细胞外游离D-丝氨酸与L-丝氨酸、甘氨酸、L-谷氨酸的含量。内侧前额叶皮质和纹状体的透析液中含有大量的D-丝氨酸，而小脑透析液中只含有微量的D-氨基酸。内侧前额叶皮质灌流钠通道激动剂藜芦碱，以河豚毒素敏感的方式增加细胞外甘氨酸和L-谷氨酸的释放，但轻微减少D-丝氨酸的释放。此外，通过局部注射喹啉酸类兴奋性毒素选择性破坏额叶内侧区神经元胞体，可显著降低前额叶灌注区的细胞外和组织内D-丝氨酸水平。这些发现表明，内源性Dserine可能从非神经细胞或某些特殊的神经细胞释放到细胞外空间，可能是通过载体介导的哺乳动物前额叶皮质的过程。此外，已表明内源性D-氨基酸至少部分地在神经细胞中积累或合成。

项目成果

西川 徹, 融 道男: "精神分裂病の生物学-最近の進歩 脳を知る・創る・守る 「脳の世紀」推進会議編"クバプロ.

Toru Nishikawa、Michio Toru：“精神分裂症生物学 - 最新进展：理解、创造和保护大脑，‘大脑世纪’促进委员会编辑”，Kubapro。

山本直樹, 西川 徹: "新たな抗精神病薬開発の未来.特集「抗精神病薬50年のあゆみ」"Schizophrenia Frontier. 2. 99-106 (2001)

Naoki Yamamoto、Toru Nishikawa：“新型抗精神病药物开发的未来。专题：抗精神病药物 50 年”《精神分裂症前沿》2. 99-106 (2001)。

西川 徹: "D体のアミノ酸で脳がはたらく"科学. 71. 984-988 (2001)

Toru Nishikawa：“大脑与 D-氨基酸一起工作”《科学》71. 984-988 (2001)。

西川 徹: "覚醒剤精神病の分子生理学"Current Insights in Neurological Science. 9. 2-4 (2001)

Toru Nishikawa：“兴奋性精神病的分子生理学”《神经科学最新见解》9. 2-4 (2001)。

黒田安計, 西川徹: "覚せい剤による遺伝子発現"分子精神医学. 2. 31-37 (2002)

Yasukei Kuroda、Toru Nishikawa：“兴奋剂诱导的基因表达”《分子精神病学》2. 31-37 (2002)。