The Role of Astrocytes in the Fragile X Pathogenesis

脆性X综合征（FXS）是遗传性智力残疾的最常见形式 也是自闭症谱系障碍的主要遗传原因之一。星形胶质细胞，a 一种神经胶质细胞，在大脑中执行多种任务， 调节突触发育、功能和可塑性。然而，星形胶质细胞在 神经发育障碍还不太清楚。在这份提案中，我们旨在确定 星形胶质细胞脆性X智力低下蛋白（FMRP）在神经细胞凋亡中的作用 星形胶质细胞Ca2+信号传导、突触缺陷和皮质可塑性损伤相关 关于FXS我们通过三个目标来实现这一点， Ca2+信号传导和突触蛋白运输的成像，细胞和分子技术 和老鼠的行为在目的1中，我们将研究FMRP在调节星形胶质细胞增殖中的作用， Ca2+信号。我们将在清醒的fmr1中进行星形胶质细胞Ca2+信号的体内成像， 在KO小鼠和其中FMRP选择性缺失或排他缺失的转基因小鼠中， 在星形胶质细胞中表达。在目标2中，我们将研究星形胶质细胞改变的机制， FXS中的Ca2+信号传导与细胞，分子和药理学实验。在AIM3中，我们 将检查星形胶质细胞中FMRP的缺失是否会导致基础和学习诱导的 通过电生理学和体内研究发现功能和结构突触可塑性的改变 星形胶质细胞特异性FMRP中树突棘中标记AMPAR运输的成像 敲除小鼠这项工作预计将提供重要的知识， 星形胶质细胞在FXS和有潜力确定新的治疗FXS的目标。

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and one of the main identified genetic causes of autism spectrum disorder. Astrocytes, a type of glial cells, perform multiple tasks in the brain and have been implicated in regulating synaptic development, function and plasticity. Yet the role astrocytes play in neurodevelopmental disorders is not well understood. In this proposal, we aim to identify the contribution of astroglial Fragile X Mental Retardation Protein (FMRP) to altered astrocyte Ca2+ signaling, synaptic deficits and cortical plasticity impairments associated with FXS. We approach this through three aims which utilize mouse genetics, in vivo imaging of Ca2+ signaling and synaptic protein trafficking, cell and molecular techniques and mouse behavior. In Aim 1, we will study the role of FMRP in regulating astrocytic Ca2+ signaling. We will perform in vivo imaging of astrocytic Ca2+ signaling in awake fmr1 KO mice and in transgenic mice in which FMRP is selectively deleted or exclusively expressed in astrocytes. In Aim 2, we will examine mechanisms of altered astrocytic Ca2+ signaling in FXS with cell, molecular and pharmacologic experiments. In Aim3, we will examine if loss of FMRP in astrocytes results in basal and learning-induced alterations in functional and structural synaptic plasticity by electrophysiology and in vivo imaging of tagged AMPAR trafficking in dendritic spines, in astrocyte-specific FMRP knockout mice. This work is expected to provide important knowledge about the role of astrocytes in FXS and has the potential to identify novel therapeutic targets for FXS.