Actin Regulation of Dendritic Spine Development and Plasticity

树突棘发育和可塑性的肌动蛋白调节

• 批准号: 10608784
• 负责人: James Q Zheng
• 金额: $ 61.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608784
• 关键词: Actins; Amino Acid Motifs; Binding Proteins; Biochemical; Brain; Brain Diseases; Cells; Cellular Structures; Chemical Synapse; Chemosensitization; Coupled; Coupling; Cytoskeleton; Dendritic Spines; Development; Disease; Event; Excitatory Synapse; F-Actin; Family; Filament; G Actin; Head; Image; Impairment; Learning; Length; Long-Term Potentiation; Mediating; Membrane; Memory; Mental Depression; Microfilaments; Modeling; Modification; Molecular; Morphogenesis; Morphology; Mutagenesis; Neck; Neurotransmitter Receptor; Optics; Pathologic; Physiological; Play; Polymers; Presynaptic Terminals; Proteins; Public Health; Regulation; Resolution; Role; Scaffolding Protein; Site; Structure; Surface; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; Testing; Textbooks; Thinness; Thymosin; Vertebral column; Work; cell motility; density; innovation; insight; loss of function; molecular dynamics; monomer; neural; neural circuit; neuronal circuitry; novel; optogenetics; polymerization; postsynaptic; postsynaptic density protein; presynaptic; profilin; spatiotemporal; synaptogenesis; trafficking

Project Summary Chemical synapses 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 cellular structures. How the cytoskeleton regulates postsynaptic structure, function, and modifications during plasticity, however, remains poorly understood. This proposed study aims to investigate novel actin mechanisms involving local G-actin regulation and structure-function coupling that enable the development of postsynaptic structure and specialization required for a functional synapse. Specifically, we will investigate the molecular mechanism underlying the spine enrichment of G-actin and its dynamic regulation during spine development. Furthermore, the study will a novel interaction between (+) end capping protein CP and Shank scaffolding protein in coupling the actin- based structural changes and the development of the postsynaptic specialization. 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.

项目概要 化学突触由成对的突触前和突触后末端组成。大部分都是兴奋的 突触位于树突棘上，树突棘是一种树突突起，承载着神经递质受体和 其他突触后专门化。突触是可塑的，会经历短期和长期的修改 在神经元回路的发育细化过程中，以及在学习和记忆过程中。突触 修饰涉及突触前和突触后的变化。在突触后位点，定向贩运 进出膜表面的神经递质受体被认为是长期神经递质受体的关键事件。 分别是术语增强（LTP）和术语抑制（LTD）。此外，树突棘经历快速 在塑性过程中它们的形态发生变化。控制和调节的潜在细胞机制 突触后受体和脊柱结构的这些快速变化仍有待充分阐明。这 细胞骨架控制细胞结构运动的许多（如果不是全部）方面。细胞骨架如何 然而，在可塑性过程中调节突触后结构、功能和修饰仍然很差 明白了。这项研究旨在研究涉及局部 G 肌动蛋白调节的新型肌动蛋白机制 和结构-功能耦合，促进突触后结构和专业化的发展 功能性突触所需的。具体来说，我们将研究其背后的分子机制。 G-肌动蛋白的脊柱富集及其在脊柱发育过程中的动态调节。此外，该研究将 (+) 封端蛋白 CP 和 Shank 支架蛋白之间在耦合肌动蛋白中的新相互作用 基于结构变化和突触后专业化的发展。鉴于许多神经 疾病与突触连接和可塑性的改变有关，我们希望获得更好的 了解突触可塑性的分子和细胞机制，这一点非常重要 帮助我们了解生理和病理条件下的大脑发育和功能。