Microtubule Dynamics in Neuronal Dendrites

神经元树突中的微管动力学

• 批准号: 9169775
• 负责人: Erik W Dent
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169775
• 关键词: Actins; Address; Affect; Alzheimer' s Disease; Axon; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Bundling; Calcium; Communication; Cytoskeleton; Data; Dendrites; Dendritic Spines; Development; Disease; Dynein ATPase; Exhibits; F-Actin; Fragile X Syndrome; Functional disorder; Glutamates; Golgi Apparatus; Hippocampus (Brain); Hour; Image; Intellectual functioning disability; Intracellular Transport; Kinesin; Laser Scanning Confocal Microscopy; Learning; Length; Life; Light; Lipids; Long-Term Potentiation; Maintenance; Mediating; Memory; Mental disorders; Messenger RNA; Methods; Microfilaments; Microscopy; Microtubule Polymerization; Microtubules; Molecular; Motor; N-Methyl-D-Aspartate Receptors; Nervous system structure; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurotransmitter Receptor; Organelles; Patients; Play; Process; Proteins; Research; Role; Route; Shapes; Site; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Time; Vertebral column; Work; base; depolymerization; drebrins; excitatory neuron; experience; functional plasticity; insight; nervous system disorder; neuron development; novel; polymerization; presynaptic; synaptogenesis; trafficking

PROJECT SUMMARY/ABSTRACT A functional nervous system requires both the appropriate development of dendritic spines and their functional plasticity throughout life. Because dendritic spines are the primary sites of contact with presynaptic axons in excitatory neurons of hippocampus and cortex, their structure and function have been studied in great detail. During development, spines undergo marked changes in structure, progressing from motile filopodial protrusions to stable mushroom-shaped spines. Activity-driven structural changes in spines of mature neurons also play important roles in learning and memory. It is therefore not surprising that changes in dendritic spines are one of the first harbingers of neuronal dysfunction in many developmental diseases, such as Fragile X syndrome and autism, as well as neurodegenerative diseases, such as Alzheimer's disease. Actin filaments play important roles in the formation, maintenance and plasticity of dendritic spine structure. Prominent in dendrite shafts, microtubules (MTs) function as stable railways for intracellular transport, but also exhibit bouts of rapid polymerization and depolymerization, termed dynamic instability. We discovered that MTs remain dynamic in dendrites throughout neuronal development and are capable of rapidly polymerizing into and out of dendritic spines in an activity-dependent fashion. In this proposal we will test the hypothesis that MT invasion of dendritic spines is a tightly regulated process resulting in motor-driven transport of cargo directly into and out of dendritic spines. Specifically, we will: 1) Determine the molecular mechanism by which MTs target specific spines, 2) Identify motor proteins and cargo that are transported into spines along MTs, and 3) Determine how material is transported out of spines along MTs. This work will provide fundamental insights into synaptogenesis and synaptic plasticity. Furthermore, because dendritic spines play essential roles in learning and memory and are the structures affected in numerous psychiatric and neurological diseases, these studies hold promise for novel cytoskeletal-based therapies for synaptic dysfunction.

项目总结/文摘