Control of Astrocyte Morphogenesis and Synaptogenesis by Astrocytic Neuroligins

星形胶质细胞是神经回路组装和功能所必需的。具体地说，星形胶质细胞在 通过释放可溶的突触分子以及通过接触来发育突触 与邻近神经元的依赖机制。星形胶质细胞-突触的相互作用是通过 星形胶质细胞突起的精细分支，通常包括每个星形胶质细胞数以万计的突触。 最近，Eroglu实验室发现了一种新的依赖接触的相互作用，调节着两种疾病的发展 星形胶质细胞的形态和突触发生。这种相互作用是通过星形细胞神经连接蛋白家族来调节的 以前专门在神经元中研究的细胞黏附分子。神经连接蛋白是突触后蛋白 与突触前神经尿毒素进行跨细胞连接以调节突触发生和突触 变速箱。有趣的是，Eroglu实验室发现，星形细胞神经连接蛋白的功能与 神经元神经连接蛋白，表明它们在星形胶质细胞中的表达具有重要的功能意义。具体来说， 这项研究证实，星形细胞神经连接蛋白-2的丢失足以显著减少对 星形胶质细胞的分支和破坏小鼠大脑皮质的兴奋/抑制平衡。虽然这些发现 突出星形细胞控制形态发生和突触发生的新角色--分子 星形胶质细胞神经连接蛋白相互作用的基础仍未被探索。在这里，我的目的是阐明分子 星形胶质细胞神经连接素-2参与星形胶质细胞形态发生和突触发育的机制 和突触生理学。为了做到这一点，我将使用星形细胞神经连接蛋白-2的体外和体内操作来 1)使用定量蛋白质组学发现和验证细胞内和细胞外星形细胞神经连接蛋白-2 对于调节星形胶质细胞形态发生和突触发生至关重要的结合伙伴2)评估 星形细胞神经连接素-2组织突触后膜的充分性和3)评估突触功能 星形细胞神经连接蛋白-2缺失脑。总而言之，这些研究中收集的数据将揭示星形细胞 神经连接素的相互作用控制星形胶质细胞和突触的发育，以及最终这些 各种机制汇聚在一起，影响突触传递。神经连接素类被认为与 神经发育疾病，如自闭症和精神分裂症，因此，必须了解 神经连接蛋白在大脑所有细胞类型中的综合功能。

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.