Internalization of AMPA receptors1

描述（由申请人提供）：神经元之间连接的重塑，被称为突触可塑性，对学习和记忆至关重要。突触可塑性的改变与包括精神分裂症和阿尔茨海默病在内的几种神经系统疾病的病理有关。突触可塑性的一个重要机制是调节AMPA型谷氨酸受体（AMPA Rs）进出突触的运输。我们拟研究Rab5a是否参与可塑性期间突触AMPA Rs的调节去除。初步证据表明，重组RabEa蛋白（一种介导细胞膜内运输的小GTPase）的表达可导致大鼠海马兴奋性突触特异性去除AMPA Rs。我们将使用Sindbis病毒表达系统在大鼠海马的器官型切片培养中表达重组Rab5a构建体和/或AMPA R的特定亚基（GluR1-3）。受体运输将通过电生理学、生物化学和免疫金电子显微镜进行监测。我们提出，描绘rab5a介导的AMPA Rs运输的信号通路可以更好地理解改变突触可塑性的神经系统疾病，并为学习和记忆过程提供更深入的了解。

DESCRIPTION (provided by applicant): The remodeling of connections between neurons, known as synaptic plasticity, is essential for learning and memory. Alterations in synaptic plasticity have been implicated in the pathology of several neurological disorders, including schizophrenia and Alzheimer's disease. One important mechanism for synaptic plasticity is the regulated trafficking of AMPA-type glutamate receptors (AMPA Rs) in and out of synapses. We propose to investigate whether Rab5a is involved in the regulated removal of synaptic AMPA Rs during plasticity. Preliminary evidence suggests that expression of a recombinant RabEa protein, a small GTPase that mediates intracellular membrane trafficking, results in the specific removal of AMPA Rs from excitatory synapses in the rat hippocampus. We will use the Sindbis virus expression system to express recombinant Rab5a constructs and/or specific subunits of the AMPA R (GluR1-3) in organotypic slice cultures of the rat hippocampus. Receptor trafficking will be monitored by electrophysiology, biochemistry, and immunogold electron microscopy. We propose that delineating the signaling pathways involved in Rab5a-mediated trafficking of AMPA Rs could lead to a better understanding of neurological disorders that alter synaptic plasticity and provide a greater insight into learning and memory processes.