The Role of Astrocytes in the Fragile X Pathogenesis

脆性X综合征(FXS)是最常见的遗传性智能障碍 也是自闭症谱系障碍的主要遗传原因之一。星形胶质细胞，一个 一种神经胶质细胞，在大脑中执行多项任务，并被认为与 调节突触的发育、功能和可塑性。然而，星形胶质细胞在其中扮演的角色 神经发育障碍还没有被很好地理解。在这项提案中，我们的目标是确定 星形胶质细胞脆性X智力低下蛋白(FMRP)在改变中的作用 星形胶质细胞钙信号、突触缺陷和皮质可塑性损伤 使用FXS。我们通过在活体内利用小鼠遗传学的三个目的来实现这一点 钙信号和突触蛋白转运的成像、细胞和分子技术 和老鼠的行为。在目标1中，我们将研究FMRP在调节星形细胞生长中的作用 钙离子信号转导。我们将在清醒的fmr1中进行星形胶质细胞钙信号的体内成像。 KO小鼠和FMRP选择性缺失或独占的转基因小鼠 在星形胶质细胞中表达。在目标2中，我们将研究星形细胞改变的机制。 细胞、分子和药理学实验研究FXS中的钙信号转导机制。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 电生理学和体内对功能和结构突触可塑性的改变 星形胶质细胞特异性FMRP中标记的AMPAR在树突棘中运输的成像 基因敲除老鼠。这项工作有望提供关于 FXS中的星形胶质细胞，并有可能发现FXS的新治疗靶点。

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.