The Endocytic Machinery of Dendritic Spines

树突棘的内吞机制

• 批准号: 7789589
• 负责人: MICHAEL D EHLERS
• 金额: $ 33.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789589
• 关键词: AMPA Receptors; Address; Autistic Disorder; Biological; Brain; Calcineurin; Cell Adhesion Molecules; Cell Communication; Cells; Clathrin; Complex; Coupled; Coupling; Cyclin-Dependent Kinase 5; Data; Dendritic Spines; Development; Diffusion; Dynamin; Dynamin III; Elements; Endocytosis; Epilepsy; Eukaryotic Cell; Excision; Filopodia; Genetic; Glutamate Receptor; Hippocampus (Brain); Homer 1; Homer 1a; Image; Ion Channel; Kinetics; Laboratories; Lateral; Learning; Link; Location; Maintenance; Measures; Mediating; Membrane Proteins; Memory; Mental Depression; Mental disorders; Modification; Molecular; Monitor; Morphology; Nerve; Neurologic; Neurons; Pathologic; Photobleaching; Physiological; Positioning Attribute; Postsynaptic Membrane; Presynaptic Terminals; Protein Isoforms; Proteins; Public Health; Reagent; Recycling; Regulation; Research; Resolution; Role; Schizophrenia; Signal Pathway; Signal Transduction; Slice; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic Agents; Time; Up-Regulation; Vertebral column; Work; addiction; base; brain cell; density; fluorescence imaging; insight; neural circuit; neurotransmission; new therapeutic target; novel; novel therapeutics; particle; patch clamp; postsynaptic; presynaptic; programs; public health relevance; receptor; scaffold; synaptic function; synaptogenesis

DESCRIPTION (provided by applicant): Neurotransmission requires a precise number and arrangement of receptors, ion channels, and adhesion molecules at synapses. Alteration of the localization or levels of these proteins at the postsynaptic membrane regulates synapse function, thereby strengthening or weakening synaptic connections in the brain. In all eukaryotic cells, removal of diverse surface membrane proteins occurs by clathrin-mediated endocytosis. Although previous studies have helped define the endocytic machinery in nonneuronal cells and in the presynaptic nerve terminal, the location and regulation of clathrin- mediated endocytosis within postsynaptic compartments and its functional role in synaptic signaling remain poorly understood. To address these important questions, my laboratory has initiated a program of cell biological and physiological studies to analyze the endocytic machinery of dendritic spines - the primary postsynaptic compartment in the mammalian brain. We have found that dendritic spines contain a zone of clathrin assembly and endocytosis adjacent to, but spatially segregated from, the postsynaptic density. This `endocytic zone' forms and persists over long periods of time, and it serves to concentrate cargo destined for internalization. Further, we have recently identified a direct physical link between the postsynaptic scaffold complex and clathrin endocytic machinery and found a novel requirement for localized endocytosis and recycling in maintaining a synaptically proximate pool of glutamate receptors. Taking advantage of these preliminary data and our ability to monitor and manipulate endocytosis in dendritic spines, we propose to define the underlying molecular and cellular mechanisms that form, maintain, and regulate the endocytic zone of spines, and determine the functional role of such zones in synapse maintenance and modification. This work will provide insight into fundamental mechanisms that underlie synapse formation and synaptic plasticity. Moreover, because clathrin-mediated endocytosis regulates neuronal responsiveness to a wide range of pathologic insults and therapeutic agents relevant to numerous neurologic and psychiatric diseases these studies hold promise for the development of novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: The proposed research will uncover molecular mechanisms that regulate brain cell communication at synapses. Abnormal function of synapses contributes to epilepsy, memory decline, depression, autism, schizophrenia, and addiction. By helping to understand how nerve cell synapses are adjusted during brain development and modified as we learn, the proposed research will define novel targets and therapeutic strategies for these devastating neurological and psychiatric disorders, which currently have a profound negative impact on public health.

描述(申请人提供)：神经传递需要在突触的受体、离子通道和黏附分子的精确数量和排列。这些蛋白在突触后膜上的定位或水平的改变调节突触功能，从而加强或削弱大脑中的突触连接。在所有真核细胞中，不同的表面膜蛋白的去除是通过网状蛋白介导的内吞作用进行的。尽管以前的研究已经帮助确定了非神经细胞和突触前神经末梢的内吞机制，但对突触后间隔内网状蛋白介导的内吞作用的定位和调节及其在突触信号中的功能作用仍知之甚少。为了解决这些重要的问题，我的实验室启动了一个细胞生物学和生理学研究计划，以分析树突棘的内吞机制-哺乳动物大脑中主要的突触后间隔。我们发现，树突棘包含一个与突触后密度相邻但空间上分离的网状蛋白组装和内吞作用区域。这一“内吞带”形成并持续很长一段时间，用来集中运往内化的货物。此外，我们最近发现了突触后支架复合体和笼蛋白内吞机制之间的直接物理联系，并发现了维持突触邻近的谷氨酸受体池的一种新的局部内吞和循环的要求。利用这些初步数据和我们监测和操纵树突棘内吞作用的能力，我们建议定义形成、维持和调节树突内吞带的潜在分子和细胞机制，并确定这些带在突触维持和修饰中的功能作用。这项工作将为突触形成和突触可塑性的基本机制提供洞察力。此外，由于笼蛋白介导的内吞作用调节神经元对与许多神经和精神疾病相关的广泛的病理侮辱和治疗剂的反应性，这些研究为开发新的治疗策略提供了希望。与公共健康相关：这项拟议的研究将揭示调节突触中脑细胞通信的分子机制。突触功能异常会导致癫痫、记忆力减退、抑郁、自闭症、精神分裂症和成瘾。通过帮助了解神经细胞突触在大脑发育过程中是如何调整和修改的，拟议中的研究将为这些破坏性的神经和精神疾病定义新的靶点和治疗策略，这些疾病目前对公共健康有深远的负面影响。

项目成果

Signalling mechanisms.

信号机制。

• DOI: 10.1016/j.conb.2009.07.004
• 发表时间: 2009
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Ehlers,MichaelD;Turrigiano,Gina
• 通讯作者: Turrigiano,Gina

TGF-beta signaling specifies axons during brain development.

• DOI: 10.1016/j.cell.2010.06.010
• 发表时间: 2010-07-09
• 期刊: Cell
• 影响因子: 64.5
• 作者: Yi JJ;Barnes AP;Hand R;Polleux F;Ehlers MD
• 通讯作者: Ehlers MD

Endocytic trafficking and recycling maintain a pool of mobile surface AMPA receptors required for synaptic potentiation.

• DOI: 10.1016/j.neuron.2009.05.025
• 发表时间: 2009-07-16
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Petrini, Enrica Maria;Lu, Jiuyi;Cognet, Laurent;Lounis, Brahim;Ehlers, Michael D.;Choquet, Daniel
• 通讯作者: Choquet, Daniel

Activity-induced remodeling of olfactory bulb microcircuits revealed by monosynaptic tracing.

• DOI: 10.1371/journal.pone.0029423
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Arenkiel BR;Hasegawa H;Yi JJ;Larsen RS;Wallace ML;Philpot BD;Wang F;Ehlers MD
• 通讯作者: Ehlers MD