Supramolecular Organization of the Postsynaptic Density

突触是神经元通讯的基础。正如最清楚地表明，在CA 1领域， 啮齿动物海马，突触功效可以随时间变化。这种突触调制是许多方面的基础 更高的大脑功能。它的功能障碍与发育障碍和某些类型的 癫痫，并可能是重要的各种神经精神疾病。现在人们普遍认为， 位于突触后致密物（PSD）中的蛋白质在调节突触功效中起关键作用，但是 这些蛋白质在PSD内的组织仍然很大程度上未知。阐明超分子 私营部门司的结构是这个项目的长期目标。 目前的证据表明，每个NMDA受体与许多信号，衔接， 细胞骨架蛋白形成单独的半自主信号“模块”，但现在已经了解到， 仅仅是生化抽象。这项研究将免疫金EM与高分辨率 电子层析成像，以研究NMDAR模块作为一个有组织的物理结构，确定其大小 和形状，并检查其内部组织。它还探讨了这些模块的组织， 更大的领域内的PSD，并探讨PSD的细胞骨架的关系。具体目标 1决定了NMDAR信号传导模块的形态;特异性目的2阐明了NMDAR信号传导模块的内部结构。 NMDAR模块的组织，使用免疫金映射来表征 具体目标3检查NMDAR模块沿蛋白质的分布，具体目标3检查NMDAR模块沿着蛋白质的分布。 突触并置;特异性目的4研究PSD和肌动蛋白细胞骨架之间的接触， 以及脊柱内肌动蛋白丝的组织。 这项研究计划的目的是在突触的分子信号通路的物理组织 在海马体中，重点是与一种特别重要的神经递质相关的蛋白质 NMDA受体。这项工作的成功完成将提高我们对突触 大脑中的机制，将提供新的线索，基本过程的基础学习和 记忆，并可能有助于了解各种神经，发育和精神疾病的原因 紊乱

Synapses are fundamental to neuronal communication. As most clearly demonstrated in the CA1 field of rodent hippocampus, synaptic efficacy can vary over time. This synaptic modulation underlies many aspects of higher brain function. Its dysfunction is implicated in developmental disorders and certain types of epilepsy, and may be important for a variety of neuropsychiatric diseases. It is now generally agreed that proteins lying within the postsynaptic density (PSD) play a key role in regulating synaptic efficacy, but the organization of these proteins within the PSD remains largely unknown. Elucidating the supramolecular architecture of the PSD is the long-term goal of this project. Current evidence suggests that each NMDA receptor combines with numerous signaling, adaptor, and cytoskeletal proteins to form individual semi-autonomous signaling "modules," but these are now understood only as biochemical abstractions. The proposed research combines immunogold EM with high-resolution electron tomography to study the NMDAR module as an organized physical structure, determining its size and shape, and examining its internal organization. It also explores the organization of these modules into larger domains within the PSD, and investigates the relationship of the PSD to the cytoskeleton. Specific Aim 1 determines the morphology of NMDAR signaling modules; Specific Aim 2 elucidates the internal organization of NMDAR modules, using immunogold mapping to characterize the laminar organization of four major proteins within a module; Specific Aim 3 examines the distribution of NMDAR modules along the synaptic apposition; and Specific Aim 4 investigates contacts between the PSD and the actin cytoskeleton, and the organization of actin filaments within the spine. This research proposal addresses the physical organization of molecular signaling pathways at synapses in the hippocampus, focusing on proteins associated with an especially important type of neurotransmitter receptor, the NMDA receptor. Successful completion of this work will improve our understanding of synaptic mechanisms in the brain, will provide new clues regarding fundamental processes that underlie learning and memory, and may help understand the causes of a variety of neurological, developmental, and psychiatric disorders.