Department of Biochemistry, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 31096 Haifa, Israel.
Department of Physiology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 31096 Haifa, Israel.
Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9628-9633. doi: 10.1073/pnas.1722677115. Epub 2018 Sep 5.
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 受体的内源性共激动剂，但关于其合成和突触周转率的调节知之甚少。氨基酸交换器 ASCT1（Slc1a4）和 ASCT2（Slc1a5）是调节 D-丝氨酸水平的候选者。使用 ASCT1 和 ASCT2 KO 小鼠，我们报告 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 D-丝氨酸摄取的主要系统，也可以通过异型交换输出 L-丝氨酸，为神经元提供 D-丝氨酸合成的底物。ASCT1-KO 小鼠的大脑 D-丝氨酸水平较低，同时 L-丙氨酸、L-苏氨酸和甘氨酸水平较高。ASCT1 的缺失与神经发育改变有关，包括海马体和纹状体体积减小，以及神经发育相关基因表达的变化。此外，ASCT1-KO 小鼠表现出运动功能、空间学习和情感行为缺陷，以及 D-丝氨酸与甘氨酸在调节 NMDA 受体活性中的相对贡献的变化。体内微透析显示 ASCT1-KO 小鼠细胞外 D-丝氨酸水平较低，证实了 D-丝氨酸代谢的改变。这些改变与 ASCT1 突变患者表现出的一些神经发育表型相似。ASCT1-KO 小鼠为针对 ASCT1 突变患者代谢损伤的潜在治疗干预提供了有用的模型。
