Auxiliary subunit regulation of AMPA receptor assembly and trafficking in health and disease

项目总结 调节AMPA受体的数量和组成是维持大脑的一个重要特征 功能。AMPA受体调节与许多大脑疾病有关，包括药物成瘾， 仅在美国就有2000多万患者患有这种疾病。AMPA受体是谷氨酸门控离子 负责学习和记忆过程的通道和调节失调可导致增强 相加行为。AMPA受体与不同的辅助亚基相关。这些辅助亚单位 调节两种AMPA受体在突触的功能活性表达。辅助性亚基的作用机制 对AMPA受体表达的调控知之甚少。我有初步数据显示有一类人 辅助亚基，称为Cornichon同系物，调节AMPA受体组装，特别是从 受体二聚体转变为功能四聚体(目标1)。我将评估与以下相关的人类AMPA受体变体 可能扰乱辅助亚单位相互作用并影响受体组装的神经发育障碍 (目标2)。为了评估受体的生物发生和贩运，我将采取一种新的方法，通过双重标记AMPA 受体及其辅助亚单位来识别细胞内的变化。我还将测量突触的变化 由于AMPA受体-辅助亚单位相互作用的丧失而导致的传递和可塑性。这些目标的结果 将为AMPA受体的细胞内处理和潜在的治疗途径提供深入的见解 目标。我在神经生物学方面学到的知识和从F99阶段学到的技术将对 我过渡到神经科学的博士后职位。对于K00阶段，我计划在一个 以体内电生理和成像为重点的实验室研究啮齿动物的药物成瘾过程 模型(目标3)。这项建议的最终目标是学习创新的技术来调查 分子和有机体水平，并发展专业知识和独立性，成为一名神经科学家。

PROJECT SUMMARY The regulation of the number and composition of AMPA receptors is a critical feature in maintaining brain function. AMPA receptor regulation has been implicated in numerous brain disorders including drug addiction, a disorder that affects more than 20 million patients in the US alone. AMPA receptors are glutamate-gated ion channels, responsible for the process of learning and memory, and dysregulation can lead to reinforcement of additive behaviors. AMPA receptors are associated with diverse auxiliary subunits. These auxiliary subunits regulate both AMPA receptor functional activity expression at synapses. Mechanisms of how auxiliary subunits regulate AMPA receptor expression are poorly understood. I have preliminary data indicating that a class of auxiliary subunits, called cornichon homologs, regulate AMPA receptor assembly, specifically the transition from receptor dimers into functional tetramers (Aim 1). I will evaluate human AMPA receptor variants associated with neurodevelopmental disorders that potentially disrupt auxiliary subunit interactions and affect receptor assembly (Aim 2). To evaluate receptor biogenesis and trafficking, I will take a novel approach by dual tagging AMPA receptors and their auxiliary subunits to identify intracellular changes. I will also measure changes to synaptic transmission and plasticity due to loss of AMPA receptor - auxiliary subunit interactions. Results from these aims will provide insights into the intracellular processing of AMPA receptors and potential avenues for therapeutic targets. The knowledge I gain in neurobiology and acquired techniques from the F99 Phase will be essential for my transition into a postdoctoral position in neuroscience. For the K00 Phase, I plan to pursue training in a laboratory focused on in vivo electrophysiology and imaging to investigate the process of drug addiction in rodent models (Aim 3). The ultimate goal of this proposal is to learn innovative techniques to investigate changes at the molecular and organismal level and to develop the expertise and independence to become an neuroscientist.