The Endocytic Machinery of Dendritic Spines

树突棘的内吞机制

• 批准号: 7217426
• 负责人: MICHAEL D EHLERS
• 金额: $ 33.77万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217426
• 关键词: Actins; Acute; Address; Antibodies; Biochemical; Biological; Biological Assay; Brain; Cell Adhesion Molecules; Cells; Chromosome Pairing; Clathrin; Clathrin Adaptors; Complement Receptor; Cytoskeleton; Data; Dendritic Spines; Development; Dominant-Negative Mutation; Dynamin; Electron Microscopy; Elements; Endocytosis; Eukaryotic Cell; Excision; Filopodia; Fractionation; Guanosine Triphosphate Phosphohydrolases; Hippocampus (Brain); Image; Individual; Ion Channel; Label; Laboratories; Lasers; Lateral; Life; Location; Measures; Mediating; Membrane; Membrane Proteins; Mental disorders; Molecular; Monitor; Morphology; Movement; Nature; Nerve; Neurologic; Neurons; Numbers; Pathologic; Positioning Attribute; Postsynaptic Membrane; Presynaptic Terminals; Property; Protein Isoforms; Proteins; RNA Interference; Range; Regulation; Resolution; Rodent; Role; Shapes; Signal Transduction; Space Perception; Surface; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic Agents; Time; Transcription Factor AP-2 Alpha; Vertebral column; Work; base; cellular imaging; chromophore; density; extracellular; immunocytochemistry; insight; neurotransmission; novel therapeutics; patch clamp; postsynaptic; presynaptic; programs; receptor; research study; scaffold; size; synaptic function; synaptogenesis; uptake

DESCRIPTION (provided by applicant): Neurotransmission requires a precise number and arrangement of receptors, ion channels, and adhesion molecules at synapses. Alterations in 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 membrane proteins of diverse types occurs by clathrin-mediated endocytosis. Although previous studies have helped define the endocytic machinery in nonneuronal cells and the presynaptic nerve terminal, the location and regulation of clathrin-mediated endocytosis within postsynaptic compartments and its functional role in synaptic signaling remain unknown. To address these important questions, my laboratory has initiated a program of biochemical and cell biological studies to analyze the endocytic machinery of dendritic spines - the primary postsynaptic compartment in the mammalian brain. We have recently 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 independent of synaptic activity, and serves to concentrate cargo destined for internalization. Taking advantage of these preliminary data and our ability to monitor and manipulate clathrin assembly and cargo uptake in neurons, we propose to define the underlying molecular and cellular mechanisms that form, maintain and regulate the endocytic zone of spines, and determine the functional consequences for spine maturation and synaptic transmission. 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.

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