Journal Article

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

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

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Alanine / Amino Acid Transport System ASC - genetics / Amino Acid Transport System ASC - metabolism / Amino acids / Animals / Astrocytes / Astrocytes - physiology / Behavior disorders / Biological Sciences / Brain / Brain - cytology / Brain - diagnostic imaging / Brain - embryology / Brain - physiology / Cell Communication - physiology / Cognitive science / D-Serine / Disease Models, Animal / Emotional behavior / Extracellular matrix / Gene expression / Glutamic acid receptors (ionotropic) / Glycine / Glycine - metabolism / HEK293 Cells / Hippocampus / Humanities and Social Sciences / Humans / L-Alanine / L-Serine / Life Sciences / Long-Term Potentiation - physiology / Magnetic Resonance Imaging / Male / Metabolic disorders / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Microcephaly - diagnostic imaging / Microcephaly - genetics / Microcephaly - metabolism / Microcephaly - pathology / Microdialysis / Minor Histocompatibility Antigens - genetics / Minor Histocompatibility Antigens - metabolism / Motor skill learning / Mutation / N-Methyl-D-aspartic acid receptors / Neostriatum / Nervous system / Neurons / Neurons - physiology / Neuroscience / Patients / Phenotypes / Primary Cell Culture / Psychology / Rats / Rats, Sprague-Dawley / Receptors / Receptors, N-Methyl-D-Aspartate - metabolism / Serine - metabolism / Spatial discrimination learning / Substrates / Synaptic Transmission - physiology / Synthesis / Therapeutic applications / Threonine