Microtubule Dynamics in Neuronal Dendrites

神经元树突中的微管动力学

• 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
• 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' 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

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.

项目摘要/摘要 一个有功能的神经系统既需要树突棘的适当发育，也需要它们的 整个生命的功能可塑性。因为树突棘是与 海马区和皮层兴奋性神经元突触前轴突的结构和功能 已经进行了非常详细的研究。在发育过程中，脊椎的结构发生了显著的变化， 从活动的丝状突起进化成稳定的蘑菇状刺。活动驱动型 成熟神经元脊椎的结构变化在学习和记忆中也发挥着重要作用。它是 因此，树突棘的变化是神经元化的最早先兆之一也就不足为奇了。 许多发育疾病的功能障碍，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。肌动蛋白细丝在细胞周期中起着重要作用。 树突棘结构的形成、维持和可塑性。突出在树枝状的竖井中， 微管是细胞内运输的稳定通道，但也表现出快速的运动。 聚合和解聚，称为动态不稳定性。我们发现MTS仍然存在 在神经元发育过程中树突的动态变化，并能够快速聚合成和 以一种依赖于活动的方式从树突棘中脱出。在这个提案中，我们将检验假设 树突棘的MT入侵是一个严格控制的过程，导致由机动驱动的货物运输。 直接进出树枝状刺。具体地说，我们将：1)通过以下方式确定分子机制 哪些MT针对特定的脊椎，2)识别被运输到脊椎的马达蛋白质和货物 以及3)确定材料如何沿MTS从脊椎中传输出来。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，因为树枝状刺 在学习和记忆中起着至关重要的作用，这些结构在许多精神和心理疾病中都受到影响 神经疾病，这些研究为突触的基于细胞骨架的新疗法带来了希望 功能障碍。