TY - JOUR
T1 - ASCT1 (Slc1a4) transporter is a physiologic regulator of brain D-serine and neurodevelopment
AU - Kaplan, Eitan
AU - Zubedat, Salman
AU - Radzishevsky, Inna
AU - Valenta, Alec C.
AU - Rechnitz, Ohad
AU - Sason, Hagit
AU - Sajrawi, Clara
AU - Bodner, Oded
AU - Konno, Kohtarou
AU - Esaki, Kayoko
AU - Derdikman, Dori
AU - Yoshikawa, Takeo
AU - Watanabe, Masahiko
AU - Kennedy, Robert T.
AU - Billard, Jean Marie
AU - Avital, Avi
AU - Wolosker, Herman
N1 - Publisher Copyright: © 2018 National Academy of Sciences. All rights reserved.
PY - 2018/9/18
Y1 - 2018/9/18
N2 - 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.
AB - 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.
KW - ASCT1
KW - D-serine
KW - Glycine
KW - Slc1a4
KW - Slc1a5
UR - http://www.scopus.com/inward/record.url?scp=85053462371&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1722677115
DO - https://doi.org/10.1073/pnas.1722677115
M3 - مقالة
C2 - 30185558
SN - 0027-8424
VL - 115
SP - 9628
EP - 9633
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 38
ER -