Synaptic Targeting of NMDA Receptors

描述(由申请人提供)：兴奋性突触上谷氨酸受体的数量和功能的使用依赖的变化改变了整个生命的神经交流。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、神经疾病和包括成瘾在内的精神障碍中发挥着核心作用。控制NMDA受体信号传递的一个主要机制是准确调节存在于突触的NMDA受体的数量。虽然对AMPA型谷氨酸受体的认识最为广泛，但对突触后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不可或缺的特征。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，我的实验室启动了一个生化和细胞生物学研究计划，以分析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，内质网(ER)的输出是NMDA受体突触传递的活性依赖的检查点，此外，我们已经在NMDA受体亚单位中确定了控制正向运输的关键分子决定因素，并发展了光学成像方法来可视化活的树突的分泌运输。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受体细胞内运输来影响突触修饰。这项工作将为突触形成和可塑性的基本机制提供亟需的见解。此外，由于NMDA受体参与了一系列神经疾病、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提供了希望。

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.