ASCT1 (Slc1a4) transporter is a physiologic regulator of brain D-serine and neurodevelopment

Eitan Kaplan, Salman Zubedat, Inna Radzishevsky, Alec C. Valenta, Ohad Rechnitz, Hagit Sason, Clara Sajrawi, Oded Bodner, Kohtarou Konno, Kayoko Esaki, Dori Derdikman, Takeo Yoshikawa, Masahiko Watanabe, Robert T. Kennedy, Jean Marie Billard, Avi Avital, Herman Wolosker

Research output: Contribution to journalArticlepeer-review


D-serine is a physiologic coagonist of NMDA receptors, but little is known about the regulation of its synthesis and synaptic turnover. The amino acid exchangers ASCT1 (Slc1a4) and ASCT2 (Slc1a5) are candidates for regulating D-serine levels. Using ASCT1 and ASCT2 KO mice, we report that ASCT1, rather than ASCT2, is a physiologic regulator of D-serine metabolism. ASCT1 is a major D-serine uptake system in astrocytes and can also export L-serine via heteroexchange, supplying neurons with the substrate for D-serine synthesis. ASCT1-KO mice display lower levels of brain D-serine along with higher levels of L-alanine, L-threonine, and glycine. Deletion of ASCT1 was associated with neurodevelopmental alterations including lower hippocampal and striatal volumes and changes in the expression of neurodevelopmental-relevant genes. Furthermore, ASCT1-KO mice exhibited deficits in motor function, spatial learning, and affective behavior, along with changes in the relative contributions of D-serine vs. Glycine in mediating NMDA receptor activity. In vivo microdialysis demonstrated lower levels of extracellular D-serine in ASCT1-KO mice, confirming altered D-serine metabolism. These alterations are reminiscent of some of the neurodevelopmental phenotypes exhibited by patients with ASCT1 mutations. ASCT1-KO mice provide a useful model for potential therapeutic interventions aimed at correcting the metabolic impairments in patients with ASCT1 mutations.

Original languageEnglish
Pages (from-to)9628-9633
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
StatePublished - 18 Sep 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.


  • ASCT1
  • D-serine
  • Glycine
  • Slc1a4
  • Slc1a5

ASJC Scopus subject areas

  • General


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