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

• 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
• 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

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，具有成千上万的精细过程，它们相互联系和相互作用

项目成果

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

Cell adhesion molecules regulating astrocyte-neuron interactions.

• DOI: 10.1016/j.conb.2021.03.015
• 发表时间: 2021-08
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Tan CX;Eroglu C
• 通讯作者: Eroglu C

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

δ-Catenin controls astrocyte morphogenesis via layer-specific astrocyte-neuron cadherin interactions.

• DOI: 10.1083/jcb.202303138
• 发表时间: 2023-11-06
• 期刊: The Journal of cell biology