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.

d-丝氨酸是NMDA受体的生理激动剂，但对其合成和突触周转的调控知之甚少。氨基酸交换剂ASCT1（Slc1a4）和ASCT2（Slc1a5）是调节d-丝氨酸水平的候选物。我们报告使用ASCT1和ASCT2 KO小鼠，ASCT1，而不是ASCT2，是d-丝氨酸代谢的生理调节剂。ASCT1是星形胶质细胞中主要的d-丝氨酸摄取系统，还可以通过异质交换输出l-丝氨酸，为神经元提供d-丝氨酸合成的底物。ASCT1-KO小鼠显示脑水平较低ð沿着具有较高水平的丝氨酸升丙氨酸，升-苏氨酸和甘氨酸。ASCT1的删除与神经发育的改变有关，包括海马和纹状体的下体积以及神经发育相关基因表达的改变。此外，ASCT1-KO小鼠在介导NMDA受体活性方面表现出运动功能，空间学习和情感行为方面的缺陷，以及d-丝氨酸与甘氨酸的相对贡献的变化。体内微透析显示ASCT1-KO小鼠体内胞外d-丝氨酸水平较低，证实d改变-丝氨酸代谢。这些改变使人联想到具有ASCT1突变的患者表现出的一些神经发育表型。ASCT1-KO小鼠为潜在的治疗干预措施提供了有用的模型，旨在纠正ASCT1突变患者的代谢障碍。