Cytoskeletal Dynamics in Neuronal Dendrites

神经元树突的细胞骨架动力学

基本信息

批准号：
8527859
负责人：
Erik W Dent
金额：
$ 30.08万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
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/8527859
关键词：
Actins Address Adult Affect Agaricales Alzheimer&apos 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

项目摘要

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一生的树突状刺和其功能可塑性的适当发展。由于树突状棘是海马和皮质兴奋性神经元中与突触前轴突接触的主要部位，因此对其结构和功能进行了详细研究。肌动蛋白丝（F-肌动蛋白）在树突状脊柱结构的形成，维持和可塑性中起着重要作用。但是，MT在脊柱结构中的作用很少研究，因为棘被认为没有MT。 MT在树突轴中突出，假定MT仅充当细胞内运输的稳定铁路。然而，MTS表现出快速聚合和解聚的爆发，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性，并能够迅速延伸到树突状丝状丝虫和培养的皮质和海马神经元的棘突。使用总反射荧光显微镜（TIRFM），我们表明树突状刺的MT入侵可能与脊柱头的快速形态学变化有关。这些发现表明，动态MT可能在脊柱结构和功能中起重要作用。实际上，许多在MTS（脂质，蛋白质，RNA，细胞器）上运输的组件或与其生长尖端相关联的组件都可以通过MTS本身直接进入刺。在此提案中，我们将检验以下假设：动态MT进入树突状刺是以调节的方式进行的，这是脊柱发育和可塑性所必需的。具体而言，我们将：1）表征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，以及3）研究基于MT的突触成分对树突状刺的靶向。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，由于树突状棘是在许多精神病和神经系统疾病中受到影响的部位，因此，这些研究对基于细胞骨架的新型基于突触功能障碍的疗法有望。公共卫生相关性：有许多发育和成人发作神经系统疾病，包括智力低下，自闭症，癫痫和阿尔茨海默氏病，会影响神经元的形状，从而影响大脑中神经元之间的沟通。这项研究将确定并表征一种新型的细胞内机制，该机制调节了成分向神经元的特定区域的定向运动并控制神经元的形状，从而为改善这些疾病的疗法提供了潜在的靶标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The dynamic cytoskeleton: backbone of dendritic spine plasticity.

DOI：
10.1016/j.conb.2010.08.013
发表时间：
2011-02
期刊：
Current opinion in neurobiology
影响因子：
5.7
作者：
Dent EW;Merriam EB;Hu X
通讯作者：
Hu X

Branch management: mechanisms of axon branching in the developing vertebrate CNS.

DOI：
10.1038/nrn3650
发表时间：
2014-01
期刊：
NATURE REVIEWS NEUROSCIENCE
影响因子：
34.7
作者：
Kalil, Katherine;Dent, Erik W.
通讯作者：
Dent, Erik W.

The F-BAR protein CIP4 inhibits neurite formation by producing lamellipodial protrusions.

DOI：
10.1016/j.cub.2012.01.038
发表时间：
2012-03-20
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Saengsawang, Witchuda;Mitok, Kelly;Viesselmann, Chris;Pietila, Lauren;Lumbard, Derek C.;Corey, Seth J.;Dent, Erik W.
通讯作者：
Dent, Erik W.

BDNF-induced increase of PSD-95 in dendritic spines requires dynamic microtubule invasions.

DOI：
10.1523/jneurosci.2445-11.2011
发表时间：
2011-10-26
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Hu X;Ballo L;Pietila L;Viesselmann C;Ballweg J;Lumbard D;Stevenson M;Merriam E;Dent EW
通讯作者：
Dent EW

Signaling to the microtubule cytoskeleton: an unconventional role for CaMKII.