Homeostatic control of the NMDA receptor co-agonist D-serine by SLC1A4

NMDA受体(NMDAR)参与从神经发育到 学习和记忆。NMDAR信号转导障碍与几种神经系统相关 疾病。越来越多的证据表明，内源性共同激动剂D-丝氨酸在 在皮质突触NMDARs的激活中起着重要作用。然而，存在着显著的差距。 在我们对大脑D-丝氨酸稳态参与的生理机制的理解中 以及它们对NMDAR信号的潜在影响。我们的初步数据表明，SLC1A4，a SLC1溶质载体家族中的中性氨基酸转运体Paralog，包括 谷氨酸转运体，出人意料地调节D-丝氨酸的跨膜通量。我们将测试 假设SLC1A4实际上是钠依赖的D-丝氨酸摄取的主要途径 大脑和从羟脯氨酸药效团开发的选择性SLC1A4抑制剂可以 改变D-丝氨酸稳态，从而调节NMDAR功能和突触可塑性。我们 也将表征最近发现的人类突变的结构和功能 编码SLC1A4的基因与神经发育和认知缺陷有关，我们将 创建并研究这种人类疾病的转基因小鼠模型。

NMDA receptors (NMDARs) participate in processes ranging from neural development to learning and memory. Disorders of NMDAR signaling are linked to several neurological diseases. Accumulating evidence suggests that the endogenous co-agonist D-serine plays a prominent role in activation of synaptic NMDARs in cortex. However, there are significant gaps in our understanding of the physiological mechanisms involved in D-serine homeostasis in brain and their potential impact on NMDAR signaling. Our preliminary data suggest that SLC1A4, a neutral amino acid transporter paralog within the SLC1 solute carrier family that includes glutamate transporters, unexpectedly mediates transmembrane flux of D-serine. We will test the hypotheses that SLC1A4 is in fact the major route of sodium-dependent D-serine uptake in brain and that selective SLC1A4 inhibitors developed from a hydroxyproline pharmacophore can alter D-serine homeostasis and thereby modulate NMDAR function and synaptic plasticity. We will also characterize the structure and function of a recently identified mutation in the human gene encoding SLC1A4 that is linked to neurodevelopmental and cognitive deficits, and we will create and study a transgenic mouse model of this human disease.