Cytoskeletal Dynamics in Neuronal Dendrites

神经元树突的细胞骨架动力学

• 批准号: 8312598
• 负责人: Erik W Dent
• 金额: $ 31.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312598
• 关键词: Actins; Address; Adult; Affect; Agaricales; Alzheimer' s Disease; Architecture; Area; Autistic Disorder; Axon; Biological Assay; Brain; Calcium; Communication; DLG4 gene; Dendrites; Dendritic Spines; Development; Disease; Endosomes; Epilepsy; Exhibits; F-Actin; Filopodia; Fluorescence Microscopy; Functional disorder; Head; Health; Hippocampus (Brain); Image; Intracellular Transport; Learning; Life; Lipids; Long-Term Depression; Maintenance; Measures; Memory; Mental Retardation; Mental disorders; Microfilaments; Microtubules; Mitochondria; Monitor; Morphology; Movement; N-Methyl-D-Aspartate Receptors; Nervous system structure; Neurons; Organelles; Pharmaceutical Preparations; Pharmacological Treatment; Play; Principal Investigator; Proteins; RNA; Research; Role; Shapes; Site; Structure; Synapses; Synaptic plasticity; Testing; Tubulin; Vertebral column; Work; base; density; depolymerization; excitatory neuron; insight; nervous system disorder; neuron development; novel; polymerization; postsynaptic; presynaptic; programs; receptor; research study; synaptogenesis; trafficking

DESCRIPTION: 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. Actin filaments (f-actin) play prominent roles in the formation, maintenance and plasticity of dendritic spine structure. However, the role of MTs in spine architecture has been studied little because spines are thought to be devoid of MTs. Prominent in dendrite shafts, MTs are assumed to function exclusively as stable railways for intracellular transport. However, MTs exhibit bouts of rapid polymerization and depolymerization, termed dynamic instability. Surprisingly, we discovered that MTs remain dynamic throughout neuronal development and are capable of rapidly extending into and out of dendritic filopodia and spines of cultured cortical and hippocampal neurons. Using total internal reflection fluorescence microscopy (TIRFM), we show that MT invasion of dendritic spines can be associated with rapid morphological changes of the spine head. These findings suggest that dynamic MTs may be playing an important role in spine structure and function. Indeed, many of the components that are either transported on MTs (lipids, proteins, RNA, organelles) or are associated with their growing tips would be capable of directly entering spines via MTs themselves. In this proposal we will test the hypothesis that dynamic MT entry into dendritic spines occurs in a regulated fashion and is required for spine development and plasticity. Specifically, we will: 1) Characterize the role of MT dynamics in spine morphology and maturation, 2) Determine how MTs affect synaptic activity and spine plasticity, and 3) Investigate MT-based targeting of synaptic components to dendritic spines. This work will provide fundamental insights into synaptogenesis and synaptic plasticity. Furthermore, because dendritic spines are the sites that are affected in numerous psychiatric and neurological diseases these studies hold promise for novel cytoskeletal-based therapies for synaptic dysfunction. PUBLIC HEALTH RELEVANCE: There are many developmental and adult onset neurological diseases, including mental retardation, autism, epilepsy, and Alzheimer's disease, that affect neuronal shape and therefore communication between neurons in the brain. This research will identify and characterize a novel intracellular mechanism that regulates directed movement of components to specific regions of the neuron and controls neuronal shape, thereby providing potential targets for therapies directed at ameliorating these diseases.

描述：功能性神经系统需要树突棘的适当发育及其在整个生命过程中的功能可塑性。由于树突棘是海马和皮层兴奋性神经元突触前轴突接触的主要部位，因此它们的结构和功能已被详细研究。肌动蛋白丝（f-肌动蛋白）在树突棘结构的形成、维持和可塑性中发挥着重要作用。然而，人们对 MT 在主干架构中的作用的研究很少，因为主干被认为缺乏 MT。 MT 在树突轴中突出，被认为专门充当细胞内运输的稳定铁路。然而，MT 表现出快速聚合和解聚的过程，称为动态不稳定性。令人惊讶的是，我们发现 MT 在整个神经元发育过程中保持动态，并且能够快速延伸进出培养的皮层和海马神经元的树突状丝状伪足和棘。使用全内反射荧光显微镜（TIRFM），我们发现树突棘的MT侵入可能与棘头的快速形态变化有关。这些发现表明动态 MT 可能在脊柱结构和功能中发挥着重要作用。事实上，许多在微管上运输的成分（脂质、蛋白质、RNA、细胞器）或与其生长尖端相关的成分能够通过微管本身直接进入脊柱。在本提案中，我们将测试这样的假设：动态 MT 进入树突棘是以受调控的方式发生的，并且是树突棘发育和可塑性所必需的。具体来说，我们将：1）描述 MT 动力学在脊柱形态和成熟中的作用，2）确定 MT 如何影响突触活动和脊柱可塑性，3）研究基于 MT 的突触成分对树突棘的靶向。这项工作将为突触发生和突触可塑性提供基本见解。此外，由于树突棘是许多精神和神经疾病受影响的部位，这些研究有望为突触功能障碍提供基于细胞骨架的新型疗法。 公众健康相关性：许多发育性和成人发病的神经系统疾病，包括智力低下、自闭症、癫痫和阿尔茨海默病，都会影响神经元的形状，从而影响大脑中神经元之间的交流。这项研究将确定并表征一种新型细胞内机制，该机制可调节成分向神经元特定区域的定向运动并控制神经元形状，从而为改善这些疾病的治疗提供潜在靶标。