Synaptic Targeting of NMDA Receptors

描述（由申请人提供）：兴奋性突触处谷氨酸受体的数量和功能的使用依赖性变化会在整个生命过程中改变神经通信。在谷氨酸门控离子通道中，N-甲基-D-天冬氨酸（NMDA）受体在突触形成、突触可塑性、神经系统疾病和精神疾病（包括成瘾）中发挥核心作用。控制NMDA受体信号传导的主要机制是精确调节存在于突触处的NMDA受体的数量。虽然AMPA型谷氨酸受体是最受欢迎的，但突触后NMDA受体数量的动态调节越来越被认为是突触成熟和突触可塑性的一个组成部分。然而，人们对NMDA受体进出突触的分子机制知之甚少。为了解决这些重要的问题，我的实验室已经启动了一项生化和细胞生物学研究计划，以分析NMDA受体的贩运和神经元活动对这种贩运的调节。我们最近发现，出口从内质网（ER）作为一个活动依赖性的检查点的突触传递的NMDA受体，此外，我们已经确定了关键的分子决定因素内的NMDA受体亚基，控制向前贩运，并开发了光学成像方法，可视化分泌贩运在生活树突。利用这些初步的数据，我们建议定义的基本细胞机制，控制NMDA受体分泌贩运，并确定如何活动指导NMDA受体胞内转运突触修饰的效果。这项工作将提供急需的了解突触形成和可塑性的基本机制。此外，由于NMDA受体参与了广泛的神经系统疾病，精神疾病和成瘾状态的发病机制，这些研究有望开发新的治疗策略。

DESCRIPTION (provided by applicant): Neural communication is modified throughout life by use-dependent changes in the number and function of glutamate receptors at excitatory synapses. Among the glutamate-gated ion channels, N-methyl-D-aspartate (NMDA) receptors play a central role in synapse formation, synaptic plasticity, neurological diseases, and psychiatric disorders including addiction. A principal mechanism controlling NMDA receptor signaling is accurate regulation of the number of NMDA receptors present at the synapse. Although most widely appreciated for AMPA-type glutamate receptors, dynamic regulation of the number of postsynaptic NMDA receptors is increasingly recognized as an integral feature of synapse maturation and synaptic plasticity. And yet, little is known about the molecular mechanisms for trafficking NMDA receptors to and from the synapse. To address these important questions, my laboratory has initiated a program of biochemical and cell biological studies to analyze the trafficking of NMDA receptors and the regulation of such trafficking by neuronal activity. We have recently found that export from the endoplasmic reticulum (ER) serves as an activity-dependent checkpoint for the synaptic delivery of NMDA receptors, Moreover, we have identified key molecular determinants within NMDA receptor subunits that control forward trafficking, and developed optical imaging approaches to visualize secretory trafficking in living dendrites. Taking advantage of these preliminary data, we propose to define the underlying cellular mechanisms that control NMDA receptor secretory trafficking, and to determine how activity directs NMDA receptor intracellular transport to effect synapse modification. This work will provide much-needed insight into fundamental mechanisms of synapse formation and plasticity. Moreover, because NMDA receptors participate in the pathogenesis of a wide range of neurologic disorders, psychiatric disease, and states of addiction, these studies hold promise for the development of novel therapeutic strategies.