Control of Tripartite Synapse Formation by Astrocytic Neuroligins

星形胶质细胞 Neuroligins 对三联突触形成的控制

基本信息

批准号：
8911667
负责人：
Jeff Alan Stogsdill
金额：
$ 4.31万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911667
关键词：
Adaptor Signaling Protein Adherence Adhesions Architecture Astrocytes Autistic Disorder Axon Binding Biological Assay Brain Brain Diseases Cell Adhesion Molecules Cell Culture System Cells Cellular biology Cognition Complex Data Dendrites Development Disease Electron Microscopy Electrophysiology (science)Epilepsy Event Evolution Excitatory Synapse Eye Family Gene Expression Homeostasis In Vitro Inhibitory Synapse Intercellular Junctions Ions Label Learning Light Link Measures Memory Mental Depression Molecular Morphology Mus Neuraxis Neurodevelopmental Disorder Neuronal Plasticity Neurons Outcome Physiology Play Presynaptic Terminals Process Proteins Publishing Regulation Research Rodent Role Signal Transduction Structure Synapses Synaptic plasticity Techniques Testing Time Trees Universities Visual Cortex Work base cognitive function extracellular functional outcomes improved in vivo learned behavior light microscopy member mutant nervous system disorder neurotransmitter release novel novel strategies postnatal postsynaptic presynaptic public health relevance research study response small hairpin RNA synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Synapses are specialized cell-cell junctions of the central nervous system (CNS) that are critical for learning, memory, and cognition. Localized to these junctions are cell adhesion molecules (CAMs) that link the presynaptic axon with the postsynaptic dendrite, which establish synaptic structure and function. CNS synapses are now considered a three-membered entity, or tripartite synapse, which include the axon terminal, the dendrite, and an ensheathing astrocyte process. Astrocytes are non-neuronal, architecturally complex cells with branches that terminate in thousands of fine processes that interact with synapses. A single mouse astrocyte can contact more than 100,000 synapses at a time. While decades of research have identified how synapses between two neurons are formed, the molecular mechanisms that regulate astrocyte-synapse interactions remain elusive. Additionally, the mechanisms and molecular links between astrocyte morphology and synapse association are unknown. Astrocyte branching complexity develops in the rodent cortex during the second postnatal week, a time of significant excitatory synapse formation. In preliminary experiments I found that astrocytes in vitro require contact with neurons to establish a complex morphology. Because astrocytes specifically contact synapses, it is likely that astrocytes express CAMs to interact with these neuronal adhesions. In preliminary experiments, I discovered that astrocytes express the neuroligin (NL) family of CAMs, which are known to play critical roles at neuronal synapses, and previously thought to be functional only in neurons. NLs are well-studied molecules that regulate synapse formation and structure of dendritic trees. Knockdown of astrocytic NLs in culture by shRNA demonstrated that NLs are required for establishing astrocyte morphology in response to neuronal contact. These data are novel and indicate that there are previously unknown functions of NLs in astrocytes, which potentially link astrocytes to synapses and control complex astrocyte architecture. Based on these observations and previously published results this proposal will utilize novel and well- established techniques to determine how NLs in astrocytes regulate synapse interaction and generate astrocyte architectural complexity. By combining cell biology, light and electron microscopy, and electrophysiology, the aims of this proposal will test the structural and functional requirement of NLs in astrocytes and identify the molecular mechanisms of astrocyte-neuron contact and downstream signaling through astrocytic NLs. The outcomes of this proposal will open exciting new avenues in studying the interactions between neurons and astrocytes throughout development and neural plasticity. NLs are associated with a number or disease states including autism and epilepsy. Therefore the proposed work will illuminate the need for reevaluation of these CAMs within the entirety of the tripartite synapse.

描述（通过应用程序证明）：突触是中枢神经系统（CNS）G，记忆和认知的专业细胞 - 细胞连接，将其定位于这些连接处是细胞粘附分子（CAM）建立突触和功能。已经确定了如何形成两个神经元之间的突触，调节星形胶质细胞伴侣相互作用的分子机制仍然难以捉摸。体外的星形细胞需要与复杂的形态相互作用这些数据是对神经元的接触。突触相互作用并通过结合细胞生物学，光和电子显微镜以及电生理学来产生星形胶质细胞体系结构。星形胶质细胞中的NL和星形胶质细胞NLS的分子机制和下游信号传导将使神经元星形胶质细胞之间的星形胶质细胞之间的变化阐明了对这些凸轮的重新评估的需求，这些凸轮乘以三方突触。