Supramolecular Organization of the Postsynaptic Density

描述（由申请人提供）：突触功效的长期修饰与学习和记忆有关;这种可塑性的功能障碍与多种神经发育和神经精神疾病有关。本项目的长期目标是阐明突触后致密物（PSD）的超分子结构，PSD在突触信号处理中起着核心作用。这些信息最终可能被证明在设计预防或治疗大脑疾病的新方法方面非常有用。该资助周期的建议包括三个具体目标：目标1是开发新的电子显微镜工具来研究突触的超微结构，并使用这些工具来研究突触的异常。 自闭症和精神分裂症小鼠模型的PSD。目的2是研究肌动蛋白丝如何附着在PSD上，研究将肌动蛋白连接到PSD的蛋白质的两种亚型的组织，并研究控制Rho家族蛋白（调节肌动蛋白重塑的分子开关）的两种PSD相关酶。目的3是研究突触前释放位点与突触后受体的排列，并探索突触粘附分子突变小鼠突触结构和受体表达的可能中断。

DESCRIPTION (provided by applicant): Long-term modifications in synaptic efficacy are implicated in learning and memory; dysfunction of this plasticity is implicated in a variety of neurodevelopmental and neuropsychiatric disorders. The long-term goal of this project is to elucidate the supramolecular organization of the postsynaptic density (PSD), which plays a central role in synaptic signal processing. This information may ultimately prove very useful in designing novel approaches to the prevention or treatment of brain disorders. The proposal for this funding cycle includes three specific aims: Aim 1 is to develop new electron microscopic tools to study the ultrastructure of synapses, and to use these tools to study abnormalities of the PSD in mouse models of autism and schizophrenia. Aim 2 is to examine how actin filaments attach to the PSD, to study the organization of two isoforms of a protein that links actin to the PSD, and to study two PSD-associated enzymes that control Rho-family proteins (molecular switches that modulate actin remodeling). Aim 3 is to study the alignment of presynaptic release sites with postsynaptic receptors, and to explore possible disruptions in synaptic structure and receptor expression in mice that have mutations in synaptic adhesion molecules.