星形胶质细胞分泌的磷脂酸在突触发育中的功能研究

Astrocytes play critical roles in synapse formation and function. However, relatively little is known about astrocyte-secreted molecules and their neuronal receptors which are important in building synapses. Our recent publication showed that astrocyte-derived phosphatidic acid (PA) could activate PKA signaling in neurons and promote dendritic branching. The secretion of PA is mainly regulated by phospholipase D1 (Pld1) which is mainly expressed by astrocyte. This proposal aims to study the role of astrocyte-secreted PA in synapse formation and its underlying mechanisms. We will use neuron-astrocyte mixed culture, neuronal culture by astrocyte conditioned medium, Pld1 conditional mutant mice and Gpr63 null mutant mice in this project. The results may provide new insight into mechanisms underlying how astrocyte regulates synapse formation.

星形胶质细胞在调节突触发育和功能方面发挥重要作用。 但是， 星形胶质细胞分泌哪些信号分子，以及它们通过神经元上的哪些受体在突触发育中扮演重要角色， 目前还知之甚少。 我们的前期工作表明，星形胶质细胞分泌的磷脂酸可以激活神经元的PKA信号通路和树突分枝。星形胶质分泌的磷脂酸主要受到磷脂酶D1 (PLD1)的调节，而PLD1主要表达在星形胶质细胞。本课题拟研究星形胶质细胞分泌的磷脂酸在突触发育中的作用及其分子机制。我们将用神经元-星形胶质共培养和星形胶质上清培养的神经元这两种体外系统，星形胶质细胞和锥体神经元特异性Pld1基因敲除小鼠以及Gpr63基因敲除小鼠这三种在体模型来达到我们的研究目标。研究结果将为星形胶质细胞如何调节突触发育提供新的机制。

本项目以小鼠海马CA1区锥体神经元上的兴奋性突触为研究对象，探讨星型胶质细胞磷脂酶D1（PLD1）及其产物磷脂酸 (PA)调节突触发育和传递的功能及机制。我们制备了星型胶质细胞内特异性Pld1基因敲除小鼠。结果表明，星型胶质细胞内的PLD1主要调节突触（树突棘）的形成。星型胶质细胞内的PLD1促进PA和脂质囊泡的分泌，PA通过作用于神经元上的GPR63受体，促进突触（树突棘）的发育。上述结果揭示了星型胶质细胞调控突触发育的新机制，将为学习记忆等生理认知的机理带来新的理解。