Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain
| Autor: | Yoshio Hirabayashi, Kenji Hamase, Albee Messing, Akira Wada, Kiyoshi Zaitsu, Norihiro Azuma, Masahiko Watanabe, Jung Hoon Yang, Kazuyuki Yoshida, Shigeyoshi Itohara, Yurika Miyoshi, Masami O. Kinoshita, Shozo Tomonaga, Takeo Machida, Shigeki Furuya, Kayoko Esaki, Tomoko Sayano |
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| Rok vydání: | 2010 |
| Předmět: |
Male
N-Methylaspartate Biology Hippocampus Biochemistry Serine Mice Neurobiology Animals Humans Phosphorylation Receptor Molecular Biology Chromatography High Pressure Liquid Phosphoglycerate Dehydrogenase Mice Knockout Glutamate receptor Brain Cell Biology Molecular biology Serine racemase Forebrain Schizophrenia NMDA receptor Female Immediate early gene Gene Deletion |
| Zdroj: | Journal of Biological Chemistry. 285:41380-41390 |
| ISSN: | 0021-9258 |
| Popis: | In mammalian brain, d-serine is synthesized from l-serine by serine racemase, and it functions as an obligatory co-agonist at the glycine modulatory site of N-methyl-d-aspartate (NMDA)-selective glutamate receptors. Although diminution in d-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor l-serine and its role in d-serine metabolism in adult brain have yet to be determined. We investigated whether l-serine synthesized in brain via the phosphorylated pathway is essential for d-serine synthesis by generating mice with a conditional deletion of d-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in l-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both l- and d-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that l-serine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steady-state levels of d-serine in adult brain. Furthermore, NMDA-evoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits l-serine availability determines the rate of d-serine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus. |
| Databáze: | OpenAIRE |
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