S1P-S1PR1 in bidirectional Neuron-Astrocyte communications

项目摘要/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、包裹和 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期重叠 发育中的大脑。神经元信号指导星形胶质细胞分化和形态成熟，而 星形胶质细胞提供代谢和营养因子来支持神经元的生存和生长。然而，分子 神经元-星形胶质细胞相互作用的调节机制和信号及其在神经元回路组装中的作用 而功能在很大程度上是未知的。我们和其他人之前已经表明，星形胶质细胞调节特定的 Hevin(SPARCL1)等几种分泌蛋白的神经回路形成、功能和可塑性 凝血酶原蛋白(TSPs)、扁桃体和去甲肾上腺素。而VGlut2的组装和可塑性需要Hevin (囊泡状谷氨酸转运体2)丘脑皮质连接，TSP促进VGlut1突触的形成。 有趣的是，这些突触蛋白的表达在发育过程中受到调节，在大脑中也会发生变化。 病理学。尽管已经做了大量的研究来识别神经元受体和 星形胶质细胞分泌的突触生成因子SPARCL1和TSPs形成突触的机制，我们不知道 了解调控它们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SPARCL1和TSP4的表达。 1-磷酸(S1P)-S1P受体1(S1PR1)。我们还发现S1PR1主要由星形胶质细胞表达 并定位于突触附近和周围的细小星形细胞突起，并驱动星形胶质细胞 形态复杂性和形态发生。尽管，S1P-S1PR信号是许多人的药物靶点 神经功能障碍，其在神经元-神经胶质细胞相互作用和神经元回路组装中的基础作用 为人所知。我们提出的研究将为神经元-星形胶质细胞的双向交流提供新的见解 通过S1P-S1PR1轴建立突触连接和功能。我们详细的机械研究 将发现S1P-S1PR1轴下游调节钙动态的新信号通路，谷氨酸 SPARCL1和TSP4在星形胶质细胞中的检测和表达这些研究也将增进我们的知识 神经元如何调控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S1P水平与SPARCL1和TSP4表达之间的机制联系 S1P/S1PR1轴在发育和疾病脑中的基础作用因此，这项提议有望 为靶向S1P/S1PR1轴减轻神经病变提供新的机制。

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.