S1P-S1PR1 in bidirectional Neuron-Astrocyte communications

项目概要/摘要 虽然突触是在神经元之间形成的，但这些结构与神经元接触， 由星形胶质细胞调节。神经元突触连接和星形胶质细胞成熟的时期重叠， 大脑发育神经元信号指示星形胶质细胞分化和形态成熟， 星形胶质细胞提供代谢和营养因子以支持神经元存活和生长。然而，分子 调节神经元-星形胶质细胞相互作用的机制和信号及其在神经元回路组装中的作用 其功能在很大程度上是未知的。我们和其他人先前已经表明，星形胶质细胞调节特定的 包括hevin（SPARCL 1）在内的几种分泌蛋白的神经回路形成、功能和可塑性， 血小板反应蛋白（TSP）、磷脂酰肌醇蛋白聚糖和Norrin。而hevin是VGlut 2+组装和可塑性的必需物质 （囊泡谷氨酸转运体2）丘脑皮质连接，TSP促进VGlut 1+突触形成。 有趣的是，这些突触形成蛋白的表达受到发育调节，并且在大脑中也发生改变。 病理学尽管已经进行了大量的研究来鉴定神经元受体， 星形胶质细胞分泌的突触发生因子SPARCL 1和TSP的突触形成机制，我们不 了解调节其在星形胶质细胞中表达的信号和机制。 我们最近发现神经元接触通过鞘氨醇刺激SPARCL 1和TSP 4的表达。 1-磷酸盐（S1 P）-S1 P受体1（S1 PR 1）。我们还发现S1 PR 1主要由星形胶质细胞表达 并定位于突触附近和周围的精细星形胶质细胞突起， 形态复杂性和形态发生。尽管S1 P-S1 PR信号传导是许多人的药物靶点， 神经系统疾病，其在神经元-胶质细胞相互作用和神经元回路组装中的基本作用并不重要 知道的我们的研究将为神经元-星形胶质细胞双向通讯提供新的视角 通过S1 P-S1 PR 1轴建立突触连接和功能。我们详细的机械研究 将确定S1 P-S1 PR 1轴下游调节钙动力学的新信号通路，谷氨酸 SPARCL 1和TSP 4在星形胶质细胞中的传感和表达。这些研究也将促进我们的知识 神经元如何调节星形胶质细胞的发育、形态发生和功能。此外，这些研究将 破译S1 P水平与SPARCL 1和TSP 4表达之间的机制联系，并阐明 S1 P/S1 PR 1轴在发育和患病脑中的基本作用。因此，该提案准备 提供靶向S1 P/S1 PR 1轴以减轻神经病理的新机制。

Project Summary/ Abstract Though synapses are formed between neurons, these structures are contacted with, ensheathed, and regulated by astrocytes. Period of neuronal synaptic connectivity and that of astrocyte maturation overlaps in developing brain. Neuronal signals instruct astrocyte differentiation and morphological maturation whereas astrocytes provide metabolic and trophic factors to support neuronal survival and growth. However, molecular mechanisms and signals that regulate neuron-astrocyte interactions and their role in neuronal circuit assembly and functions are largely unknown. We and others have previously shown that astrocytes modulate specific neural circuit formation, function and plasticity by several secreted proteins including hevin (SPARCL1), thrombospondins (TSPs), glypicans and norrin. While hevin is needed for assembly and plasticity of VGlut2+ (vesicular glutamate transporter 2) thalamocortical connections, TSPs facilitate VGlut1+ synapse formation. Intriguingly, expression of these synaptogenic proteins is developmentally regulated and are also altered in brain pathologies. Although a significant amount of research has been done to identify the neuronal receptors and mechanism of synapse formation by astrocyte-secreted synaptogenic factors SPARCL1 and TSPs, we do not know the signals and mechanisms that regulate their expression in astrocytes. We have recently found that neuronal contact stimulates expression of SPARCL1 and TSP4 via Sphingosine- 1-Phosphate (S1P)-S1P Receptor 1 (S1PR1). We also found that S1PR1 is primarily expressed by astrocytes and is localized to the fine astrocytic processes near and around the synapses and drives astrocyte morphological complexity and morphogenesis. Although, S1P-S1PR signaling is a drug target for many neurological disorders, its fundamental role in neuron-glia interactions and neuronal circuit assembly is not known. Our proposed studies will provide novel insight into the neuron-astrocyte bidirectional communication through S1P-S1PR1 axis in establishing synaptic connectivity and functions. Our detailed mechanistic studies will identify new signaling pathway downstream of S1P-S1PR1 axis in regulating calcium dynamics, glutamate sensing and expression of SPARCL1 and TSP4 in astrocytes. These studies will also advance our knowledge of how neurons regulate astrocyte development, morphogenesis and function. Moreover, these studies will decipher the mechanistic link between levels of S1P and the expression of SPARCL1 and TSP4 and clarify on the fundamental role of S1P/S1PR1 axis in the developing and diseased brain. This proposal thus is poised to provide novel mechanisms of targeting S1P/S1PR1 axis in alleviating neuropathologies.