Endogenous D-serine exists in the mammalian brain independent of synthesis by serine racemase

Akina Osaki, Marie Aoyama, Masashi Mita, Kenji Hamase, Masato Yasui, Jumpei Sasabe

Research output: Contribution to journalArticlepeer-review

Abstract

Activation of N-methyl-D-aspartate receptors (NMDARs) requires binding of a co-agonist in addition to L-glutamate. D-serine binds to the co-agonist site on GluN1 subunits of NMDARs and modulates glutamatergic neurotransmission. While loss of GluN1 subunits in mice results in neonatal death due to respiratory failure, animals that lack a D-serine synthetic enzyme, serine racemase (SR), show grossly normal growth. However, SR-independent origins of D-serine in the brain remain unclarified. In the present study, we investigated the origin of brain D-serine in mice. Loss of SR significantly reduced D-serine in the cerebral cortex, but a portion of D-serine remained in both neonates and adults. Although D-serine was also produced by intestinal bacteria, germ-free experiments did not influence D-serine levels in the cerebral cortex. In addition, treatment of SR-knockout mice with antibiotics showed a significant reduction of intestinal D-serine, but no reduction in the brain. On the other hand, restriction of dietary intake reduced systemic circulation of D-serine and resulted in a slight decrease of D-serine in the cerebral cortex, but did not account for brain D-serine found in the SR-knockout mice. Therefore, our findings show that endogenous D-serine of non-SR origin exists in the brain. Such previously unrecognized, SR-independent, endogenous D-serine may contribute baseline activity of NMDARs, especially in developing brain, which has minimal SR expression.

Original languageEnglish
Pages (from-to)186-191
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume641
DOIs
Publication statusPublished - Jan 22 2023

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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