Actin Mechanisms of Postsynaptic Structure and Function

 描述(申请人提供)：突触代表神经元通讯的基本单位，由成对的突触前和突触后终末组成。大多数兴奋性突触存在于树突棘上，这是一种树突突起，承载着神经递质受体和其他突触后特化。突触是可塑性的，在神经元电路的发育完善以及学习和记忆过程中都会经历短期和长期的修改。突触修改包括突触前和突触后的变化。在突触后部位，神经递质受体的直接转运分别被认为是长时程增强(LTP)和抑制(LTD)的关键事件。此外，树突棘在可塑性过程中会经历快速的形态变化。控制和调节这些突触后受体和脊柱结构快速变化的潜在细胞机制仍未完全阐明。细胞骨架控制着细胞结构运动的许多方面，如果不是全部的话。然而，细胞骨架如何在可塑性过程中调节突触后结构、功能和修饰仍然知之甚少。这项拟议的研究旨在阐明控制脊柱发育、动力学和功能的肌动蛋白机制。我们将利用我们在培养神经元和器官切片中研究细胞骨架动力学的成像专业知识和经验来了解肌动蛋白对突触后结构和功能的调节。具体地说，我们将检验这一新的假设，即协调的单体G-肌动蛋白定位和肌动蛋白细丝的适时末端封顶对于脊柱中时空肌动蛋白的重塑至关重要，从而在可塑性过程中奠定突触后修改的基础。鉴于许多神经功能障碍与突触连接和可塑性的改变有关，我们希望更好地了解突触可塑性的分子和细胞机制，这对于我们理解大脑在生理和病理条件下的发育和功能具有重要意义。

 DESCRIPTION (provided by applicant): Synapses represent the basic unit of neuronal communications and are composed of paired pre- and post- synaptic terminals. Most of the excitatory synapses reside on dendritic spines, a type of dendritic protrusion that hosts neurotransmitter receptors and other postsynaptic specializations. Synapses are plastic and undergo short- and long-term modifications during developmental refinement of neuronal circuitry, as well as during learning and memory. Synaptic modifications involve both pre- and post-synaptic changes. At the postsynaptic site, directed trafficking of neurotransmitter receptors to and from the membrane surface is believed to be a key event underlying long-term potentiation (LTP) and depression (LTD), respectively. In addition, dendritic spines undergo rapid changes in their morphology during plasticity. The underlying cellular mechanisms that control and regulate these rapid changes in postsynaptic receptors and spine structures remain to be fully elucidated. The cytoskeleton controls many, if not all, aspects of the motility of celllar structures. How the cytoskeleton regulates postsynaptic structure, function, and modifications during plasticity, however, remains poorly understood. This proposed study aims to elucidate the actin mechanisms that control spine development, dynamics, and function. We will take advantage of our imaging expertise and experience in studying cytoskeletal dynamics in cultured neurons and organotypic slices to understand the actin regulation of postsynaptic structure and function. Specifically, we will test the novel hypothesis that coordinated monomeric G-actin localization and timely end capping of actin filaments are essential for spatiotemporal actin remodeling in the spine to underlie postsynaptic modifications during plasticity. Given that many neural disorders are associated with alterations in synaptic connections and plasticity, we hope to gain a better understanding of the molecular and cellular mechanisms underlying synaptic plasticity, which is of importance to our understanding of brain development and functions under both physiological and pathological conditions.