Microtubule Dynamics in Neuronal Dendrites

项目总结/摘要 一个功能正常的神经系统既需要树突棘的适当发育， 在整个生命过程中的功能可塑性。因为树突棘是接触 海马和皮层兴奋性神经元中的突触前轴突，其结构和功能具有 被详细研究过了。在发育过程中，刺的结构发生了显著的变化， 从活动的丝状足突发展到稳定的蘑菇状刺。活动驱动 成熟神经元棘的结构变化在学习和记忆中也起重要作用。是 因此，树突棘的变化是神经元凋亡的第一个预兆，这并不奇怪。 许多发育性疾病的功能障碍，如脆性X综合征和自闭症，以及 神经退行性疾病，如阿尔茨海默病。肌动蛋白丝在细胞内起着重要的作用， 树突棘结构的形成、维持和可塑性。在枝晶中很突出， 微管（MT）作为细胞内运输的稳定铁路发挥作用，但也表现出快速的 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在树突中是动态的，并且能够快速聚合成和 从树突棘中分离出来。在本提案中，我们将检验以下假设： MT侵入树突棘是一个严格调控的过程，导致马达驱动的货物运输 直接进出树突棘具体来说，我们将：1）确定分子机制， 哪些MT靶向特定的刺，2）鉴定转运到刺中的马达蛋白和货物 沿着MT，以及3）确定材料如何沿着沿着MT从脊柱中运输出来。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重要作用，是许多精神病和 神经系统疾病，这些研究有望为突触 功能障碍

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.