Actin Mechanisms of Postsynaptic Structure and Function

突触后结构和功能的肌动蛋白机制

• 批准号: 8888282
• 负责人: James Q Zheng
• 金额: $ 38.19万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888282
• 关键词: Actins; Binding; Brain; Cell physiology; Cells; Chemical Synapse; Chemosensitization; Communication; Complex; Cytoskeleton; Data; Dendritic Spines; Development; Disease; Event; Excitatory Synapse; Exhibits; F-Actin; Filament; G Actin; Goals; Growth; Image; Knowledge; Learning; Long-Term Potentiation; Membrane; Memory; Mental Depression; Microfilaments; Minus End of the Actin Filament; Modification; Molecular; Morphology; Neurons; Neurotransmitter Receptor; Optics; Pattern; Physiological; Plastics; Play; Presynaptic Terminals; Protein Family; Public Health; Regulation; Role; Series; Site; Slice; Structure; Surface; Synapses; Synaptic Receptors; Synaptic plasticity; Testing; Tropomyosin; Vertebral column; Vertebrates; Work; base; cell motility; cofilin; crosslink; experience; membrane assembly; molecular imaging; monomer; neural circuit; neuronal circuitry; novel; polymerization; postsynaptic; public health relevance; receptor; relating to nervous system; research study; response; scaffold; spatiotemporal; synaptogenesis; trafficking; tropomodulin

 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.

 描述（由申请人提供）：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端组成。大多数兴奋性突触位于树突棘上，树突棘是一种树突突起，包含神经递质受体和其他突触后特化。突触是可塑的，在神经元电路的发育细化以及学习和记忆过程中会经历短期和长期的修改。突触修饰涉及突触前和突触后的变化。在突触后位点，神经递质受体进出膜表面的定向运输被认为分别是长时程增强（LTP）和抑制（LTD）的关键事件。此外，树突棘在可塑性过程中其形态发生快速变化。控制和调节突触后受体和脊柱结构这些快速变化的潜在细胞机制仍有待充分阐明。细胞骨架控制细胞结构运动的许多（如果不是全部）方面。然而，细胞骨架在可塑性过程中如何调节突触后结构、功能和修饰仍然知之甚少。这项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。我们将利用我们的成像专业知识和研究培养神经元和器官切片中细胞骨架动力学的经验来了解突触后结构和功能的肌动蛋白调节。具体来说，我们将测试新的假设，即协调单体 G 肌动蛋白定位和肌动蛋白丝的及时封端对于脊柱中的时空肌动蛋白重塑是可塑性期间突触后修饰的基础。鉴于许多神经疾病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背后的分子和细胞机制，这对于我们理解生理和病理条件下的大脑发育和功能非常重要。