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

Jung Hoon Yang, Akira Wada, Kazuyuki Yoshida, Yurika Miyoshi, Tomoko Sayano, Kayoko Esaki, Masami O. Kinoshita, Shozo Tomonaga, Norihiro Azuma, Masahiko Watanabe, Kenji Hamase, Kiyoshi Zaitsu, Takeo MacHida, Albee Messing, Shigeyoshi Itohara, Yoshio Hirabayashi, Shigeki Furuya

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Abstract

In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist 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 Dserine 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 Lserine- synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked 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 Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.

Original languageEnglish
Pages (from-to)41380-41390
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number53
DOIs
Publication statusPublished - Dec 31 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yang, J. H., Wada, A., Yoshida, K., Miyoshi, Y., Sayano, T., Esaki, K., Kinoshita, M. O., Tomonaga, S., Azuma, N., Watanabe, M., Hamase, K., Zaitsu, K., MacHida, T., Messing, A., Itohara, S., Hirabayashi, Y., & Furuya, S. (2010). 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. Journal of Biological Chemistry, 285(53), 41380-41390. https://doi.org/10.1074/jbc.M110.187443