Control of Astrocyte Development and Astrocyte-Synapse Interactions

星形胶质细胞发育和星形胶质细胞突触相互作用的控制

基本信息

批准号：
10376297
负责人：
Cagla Eroglu
金额：
$ 34.52万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376297
关键词：
Actins Address Adherence Affect Alleles Astrocytes Axon Biological Assay Brain Cell Adhesion Molecules Cells Coculture Techniques Complex Cytoskeleton Development Electron Microscopy Electrophysiology (science)Electroporation Family Fibroblasts Gene Expression Genetic Screening Homeostasis Impairment In Vitro Individual Ions Label Link Measures Mediating Modification Molecular Morphogenesis Morphology Mus Mutation Neurons Neurotransmitter Receptor Outcome Pathology Physiology Population Process Protein Family Regulation Role Scaffolding Protein Schizophrenia Synapses Synaptic plasticity System Testing Time Visual Visual Cortex addiction autism spectrum disorder base brain cell dark rearing experience experimental study extracellular in vivo mind control mouse genetics neglect nervous system disorder neural circuit neurotransmitter release novel postnatal postnatal development postsynaptic presynaptic protein function synaptic function synaptogenesis

项目摘要

Astrocytes are highly complex cells with hundreds of thousands of fine processes that contact and ensheathe neuronal synapses. These perisynaptic astrocyte processes actively participate in synaptic development and function by regulating neurotransmitter release, maintaining ion homeostasis, and modulating synaptic connectivity. Despite the importance of astrocytes in synaptic development and function, we know very little about the molecular and cellular mechanisms that control the establishment of complex astrocyte morphology and astrocyte-synapse interactions. In our preliminary experiments, we found that in the mouse visual cortex the establishment of the complex astrocyte morphology is a developmentally regulated process that occurs during a period of extensive synapse formation. Manipulation of visual experience, i.e. dark rearing mice during first three weeks of postnatal development, strongly stunts cortical astrocyte development, indicating that experience- dependent changes in synaptic connectivity can alter morphological maturation of astrocytes. How is the complex astrocyte morphology attained and remodeled? To mechanistically address this question, we developed a primary cortical neuron and astrocyte co-culture system that takes advantage of the following basic observation: Astrocytes cultured by themselves have a simple fibroblast-like morphology; however, contact with neurons, even for a short period of time, is sufficient to trigger extensive elaboration of the astrocytes. This morphological shift in astrocytes is primarily driven by direct neuronal contact, but not by soluble secreted factors. Using this system, we conducted a candidate-based genetic screen and identified that the astrocytic expression of neuroligin (NL) family cell-adhesion molecules (CAMs), NL1, NL2 and NL3 control neuronal adherence and morphological maturation of astrocytes in vitro and in vivo. Based on these findings, our objective here is to determine the functions of NLs in astrocyte development and astrocyte- synapse interactions. To do so, we will test three hypotheses: 1) Astrocytic NLs control astrocyte morphological complexity by mediating astrocyte-synapse association. 2) NLs perform these functions via their extracellular interactions with axonal/presynaptic neurexins and 3) via their critical intracellular domains that control cytoskeletal dynamics within astrocytes. These studies have the potential to significantly advance our understanding of the molecular basis of astrocyte development and astrocyte-synapse interactions. Moreover, the results obtained here will provide critical new avenues for studying the formation of the tripartite synapses and reveal a new paradigm through which astrocytic NLs control brain development, a process that may be critically impaired in neurological disorders.!

星形胶质细胞是高度复杂的细胞，具有数十万个接触和振动神经元突触。这些非突触的星形胶质细胞过程积极参与突触通过调节神经递质释放，保持离子稳态和调节突触连接。尽管星形胶质细胞在突触发育和功能中很重要，但我们对控制复合物的建立的分子和细胞机制知之甚少星形胶质细胞的形态和星形胶质细胞 - 共生相互作用。在我们的初步实验中，我们发现在小鼠视觉皮层中建立了复杂的星形胶质细胞形态是一个受发展调节的过程，发生在广泛的突触形成。操纵视觉体验，即前三个黑暗饲养小鼠数周的产后发展，强烈特技表层星形胶质细胞的发育，表明经验 - 突触连通性的依赖变化可以改变星形胶质细胞的形态成熟。怎么样复杂的星形胶质细胞形态已达到和重塑？为了从机械上解决这个问题，我们开发了一种利用以下优势的主要皮质神经元和星形胶质细胞共培养系统基本观察：自身培养的星形胶质细胞具有简单的成纤维细胞样形态。然而，即使在短时间内，与神经元接触也足以触发广泛的阐述星形胶质细胞。星形胶质细胞的形态学转变主要是由直接神经元接触驱动的，但不是由可溶的分泌因素。使用此系统，我们进行了基于候选的遗传筛查并确定神经素（NL）家族细胞粘附分子（CAM），NL1，NL2和NL3的星形细胞表达控制星形胶质细胞体外和体内的神经元粘附和形态成熟。基于这些调查结果，我们的目的是确定NLS在星形胶质细胞发育和星形胶质细胞中的功能突触相互作用。为此，我们将检验三个假设：1）星形细胞NLS控制星形胶质细胞通过介导星形胶质 - 合成关联的形态复杂性。 2）NLS通过它们与轴突/突触前神经毒素的细胞外相互作用和3）通过其临界细胞内结构域控制星形胶质细胞内的细胞骨架动力学。这些研究有可能显着促进我们对分子基础的理解星形胶质细胞发育和星形胶质细胞间隔相互作用。而且，这里获得的结果将提供研究三方突触形成的关键新途径，并通过星形细胞NLS控制大脑发育，这一过程可能严重损害神经系统疾病。！

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates.

DOI：
10.1038/s41467-023-38582-7
发表时间：
2023-06-08
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Chen, Xinhong;Wolfe, Damien A.;Bindu, Dhanesh Sivadasan;Zhang, Mengying;Taskin, Naz;Goertsen, David;Shay, Timothy F.;Sullivan, Erin E.;Huang, Sheng-Fu;Kumar, Sripriya Ravindra;Arokiaraj, Cynthia M.;Plattner, Viktor M.;Campos, Lillian J.;Mich, John K.;Monet, Deja;Ngo, Victoria;Ding, Xiaozhe;Omstead, Victoria;Weed, Natalie;Bishaw, Yeme;Gore, Bryan B.;Lein, Ed S.;Akrami, Athena;Miller, Cory;Levi, Boaz P.;Keller, Annika;Ting, Jonathan T.;Fox, Andrew S.;Eroglu, Cagla;Gradinaru, Viviana
通讯作者：
Gradinaru, Viviana

The role of astrocyte structural plasticity in regulating neural circuit function and behavior.

DOI：
10.1002/glia.24191
发表时间：
2022-08
期刊：
Glia
影响因子：
6.2
作者：
通讯作者：

HepaCAM controls astrocyte self-organization and coupling.

DOI：
10.1016/j.neuron.2021.05.025
发表时间：
2021-08-04
期刊：
Neuron
影响因子：
16.2
作者：
Baldwin KT;Tan CX;Strader ST;Jiang C;Savage JT;Elorza-Vidal X;Contreras X;Rülicke T;Hippenmeyer S;Estévez R;Ji RR;Eroglu C
通讯作者：
Eroglu C

Cell adhesion molecules regulating astrocyte-neuron interactions.