Microtubule Dynamics in Neuronal Dendrites

神经元树突中的微管动力学

基本信息

批准号：
9265534
负责人：
Erik W Dent
金额：
$ 36.24万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/9265534
关键词：
Actins Address Affect Alzheimer&apos s Disease Autistic Disorder 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 Depolymerization Microtubule Polymerization Microtubules Molecular Motor N-Methyl-D-Aspartate Receptors Nervous system structure Neurodegenerative Disorders Neuronal Dysfunction Neurons Neurotransmitter Receptor Organelles Patients Play Polymers Process Proteins Research Role Route Site Structure Synapses Synaptic plasticity Techniques Testing Time Vertebral column Work base cell motility depolymerization drebrins excitatory neuron experience functional plasticity insight nervous system disorder neuron development neurotransmitter transport novel polymerization presynaptic synaptogenesis trafficking

项目摘要

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.

项目概要/摘要功能性神经系统需要树突棘的适当发育及其终生的功能可塑性。因为树突棘是与细胞接触的主要部位海马和皮层兴奋性神经元的突触前轴突，其结构和功能与进行了非常详细的研究。在发育过程中，脊柱的结构发生显着变化，从活动的丝状伪足突起发展为稳定的蘑菇状刺。活动驱动成熟神经元棘的结构变化在学习和记忆中也发挥着重要作用。这是因此，树突棘的变化是神经元变化的第一个预兆之一也就不足为奇了。许多发育疾病的功能障碍，例如脆性 X 综合征和自闭症，以及神经退行性疾病，例如阿尔茨海默病。肌动蛋白丝在肌动蛋白丝中发挥重要作用树突棘结构的形成、维持和可塑性。突出的枝晶轴，微管（MT）作为细胞内运输的稳定铁路，但也表现出快速的波动聚合和解聚，称为动态不稳定性。我们发现MT仍然存在在整个神经元发育过程中树突处于动态状态，并且能够快速聚合成以活动依赖性方式脱离树突棘。在这个提案中，我们将测试以下假设： MT 入侵树突棘是一个严格调控的过程，导致电机驱动的货物运输直接进出树突棘。具体来说，我们将：1）通过以下方式确定分子机制：哪些 MT 靶向特定的刺，2) 识别运动蛋白和运输到刺中的货物沿着 MT，以及 3) 确定材料如何沿着 MT 传输出书脊。这项工作将提供对突触发生和突触可塑性的基本见解。此外，由于树突棘在学习和记忆中发挥着重要作用，并且是许多精神和疾病中受影响的结构神经系统疾病，这些研究为基于细胞骨架的新型突触疗法带来了希望功能障碍。