Synaptic Targeting of NMDA Receptors

描述（由申请人提供）：神经通讯在整个生命过程中通过兴奋性突触中谷氨酸受体数量和功能的使用依赖性变化而改变。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、神经系统疾病和包括成瘾在内的精神疾病中发挥核心作用。控制NMDA受体信号传导的主要机制是准确调节突触中存在的NMDA受体的数量。尽管最广泛的认识是ampa型谷氨酸受体，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整体特征。然而，关于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，我的实验室启动了一个生化和细胞生物学研究项目，分析NMDA受体的运输以及神经元活动对这种运输的调节。我们最近发现，从内质网（ER）输出作为NMDA受体突触递送的活动依赖检查点。此外，我们已经确定了NMDA受体亚基内控制正向运输的关键分子决定因素，并开发了光学成像方法来可视化活树突中的分泌运输。利用这些初步数据，我们建议定义控制NMDA受体分泌运输的潜在细胞机制，并确定活性如何指导NMDA受体细胞内运输以影响突触修饰。这项工作将为突触形成和可塑性的基本机制提供急需的见解。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，这些研究为开发新的治疗策略带来了希望。

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.