Control of Astrocyte Morphogenesis and Synaptogenesis by Astrocytic Neuroligins

星形胶质细胞 Neuroligins 控制星形胶质细胞形态发生和突触发生

• 批准号: 10187670
• 负责人: Kristina I Sakers
• 金额: $ 5.17万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187670
• 关键词: Actins; Affect; Astrocytes; Binding; Brain; Buffers; Cell Adhesion Molecules; Complex; Cytoskeletal Proteins; Cytoskeleton; Data; Development; Disease; Electrophysiology (science); Electroporation; Equilibrium; Excitatory Synapse; Family; Genes; Growth; Immunofluorescence Immunologic; In Vitro; Ions; Knockout Mice; Label; Laboratories; Link; Maintenance; Mediating; Molecular; Morphogenesis; Morphology; Mus; Mutation; N-Methyl-D-Aspartate Receptors; NR1 gene; Neurites; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurotransmitters; Pathogenesis; Physiology; Play; Process; Proteins; Proteomics; Regulation; Research; Role; Schizophrenia; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; Surface; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptosomes; Testing; Work; autism spectrum disorder; base; cell type; design; extracellular; in vivo; knock-down; nervous system disorder; neural circuit; neuroligin 2; neuron development; neuronal circuitry; novel; postnatal; protein protein interaction; recruit; scaffold; small hairpin RNA; synaptic function; synaptogenesis; transmission process

Astrocytes are essential for neural circuit assembly and function. Specifically, astrocytes play critical roles in development of synapses though release of soluble synaptogenic molecules as well as through contact- dependent mechanisms with neighboring neurons. Astrocyte-synapse interactions are mediated through the elaborate branching of astrocyte processes, often encompassing tens of thousands of synapses per astrocyte. Recently, the Eroglu lab discovered a novel contact-dependent interaction regulating both development of astrocyte morphology and synaptogenesis. This interaction is mediated through astrocytic neuroligins, a family of cell adhesion molecules previously studied exclusively in neurons. Neuroligins are post-synaptic proteins that make transcellular connections with pre-synaptic neurexins to regulate synaptogenesis and synaptic transmission. Interestingly, the Eroglu lab found that astrocytic neuroligins perform distinct functions from neuronal neuroligins, demonstrating that their expression in astrocytes is functionally significant. Specifically, this study established that loss of astrocytic neuroligin-2 is sufficient to significantly diminish elaboration of astrocyte branching and disrupt the excitation/inhibition balance in the mouse cortex. While these findings highlight a novel player in astrocytic control of morphogenesis and synaptogenesis, the molecular underpinnings of astrocytic neuroligin interactions remain unexplored. Here, I aim to elucidate the molecular mechanisms governing astrocytic neuroligin-2 involvement in astrocyte morphogenesis, synapse development and synaptic physiology. To do so, I will use both in vitro and in vivo manipulation of astrocytic neuroligin-2 to 1) use quantitative proteomics to discover and validate intracellular and extracellular astrocytic neuroligin-2 binding partners critical for regulation of astrocyte morphogenesis and synaptogenesis 2) assess the sufficiency of astrocytic neuroligin-2 to organize post-synaptic membranes and 3) assess synaptic function in astrocytic neuroligin-2 null brains. In summary, the data collected in these studies will reveal how astrocytic neuroligin interactions control development of both astrocytes and synapses and ultimately how these mechanisms converge to influence synaptic transmission. Neuroligins have been implicated in neurodevelopmental diseases such as autism and schizophrenia and therefore, it is imperative to understand the comprehensive functions of neuroligins in all cell types of the brain.

星形胶质细胞对于神经回路的组装和功能是必不可少的。具体来说，星形胶质细胞在 通过释放可溶性突触发生分子以及通过接触- 与邻近神经元的依赖机制。星形胶质细胞-突触相互作用是通过 星形胶质细胞过程的精细分支，通常每个星形胶质细胞包含数万个突触。 最近，Eroglu实验室发现了一种新的接触依赖性相互作用， 星形胶质细胞形态和突触发生。这种相互作用是通过星形胶质细胞神经连接素介导的， 以前只在神经元中研究的细胞粘附分子。神经胶素是突触后蛋白 与突触前神经毒素进行跨细胞连接，以调节突触发生和突触 传输有趣的是，Eroglu实验室发现，星形胶质细胞神经胶质素执行不同的功能， 神经元神经连接素，表明它们在星形胶质细胞中的表达在功能上是重要的。具体地说， 这项研究证实星形胶质细胞神经连接素-2的缺失足以显著减少 星形胶质细胞分支和破坏小鼠皮层中的兴奋/抑制平衡。虽然这些发现 强调了星形胶质细胞控制形态发生和突触发生的一个新的参与者， 星形胶质细胞神经连接素相互作用的基础仍然未被探索。在这里，我的目标是阐明分子 星形胶质细胞神经连接素-2参与星形胶质细胞形态发生、突触发育的机制 和突触生理学。为了做到这一点，我将在体外和体内对星形胶质细胞神经连接素-2进行操作， 1)使用定量蛋白质组学发现和验证细胞内和细胞外星形胶质细胞神经胶质素-2 对调节星形胶质细胞形态发生和突触发生至关重要的结合伴侣2）评估 星形胶质细胞神经连接素-2组织突触后膜的充分性和3）评估 星形胶质细胞神经胶质素-2缺失的大脑。总之，这些研究中收集的数据将揭示星形胶质细胞 神经连接素的相互作用控制星形胶质细胞和突触的发育，并最终如何这些 机制会聚以影响突触传递。神经胶质素与 神经发育疾病，如自闭症和精神分裂症，因此，必须了解 神经胶质素在大脑所有细胞类型中的综合功能。