Contribution of astrocytes to the Fragile X Syndrome

项目摘要 脆性X综合征（FXS）是最常见的精神发育迟滞类型，可以与单一的 基因突变FXS患者表现出许多行为改变，以及发育异常， 大脑中的突触星形胶质细胞是哺乳动物脑中主要类型的神经胶质细胞，调节突触和神经元的功能。 神经元功能，并涉及许多发育和退行性神经疾病。的 该建议的目的是确定星形胶质细胞在FXS中的作用。结合小鼠遗传学，实时成像， 突触分子谱分析、行为分析和药物干预，我们提出了3个目标。在Aim中 1，我们研究了星形胶质细胞脆性X智力低下蛋白（FMRP）缺失如何有助于突触 以及在小鼠中观察到的行为缺陷。我们将产生转基因小鼠，其中FMRP被选择性地 缺失或仅在星形胶质细胞中表达。然后，我们将比较突触和行为表型 这些小鼠与野生型对照和FMRP完全敲除小鼠的比较。目标2建立在我们早期的 观察到星形胶质细胞特异性FMRP敲除小鼠增加了未成熟树突状细胞的产生， 皮层神经元的棘。我们将联合收割机在体内成像与数学建模和突触 蛋白质组成像，以解决星形胶质细胞FMRP缺失如何影响棘发生的空间分布 对兴奋性皮质神经元以及突触/突触周围神经元和星形胶质细胞蛋白表达的影响 新形成的刺在目的3中，我们检查了FMRP被抑制的小鼠中突触的功能变化。 在星形胶质细胞中选择性缺失。特别是，我们将研究神经胶质细胞谷氨酸摄取和突触 谷氨酸浓度在星形胶质细胞特异性FMRP敲除小鼠中受到影响，并确定是否纠正 异常的谷氨酸摄取加剧了这些小鼠中的树突棘缺陷。拟议的工作将是 第一个系统的体内研究调查星形胶质细胞对FXS的贡献。通过研究星形胶质细胞在 FXS的神经病理学，这些研究将促进我们对疾病的理解，并可能指出 新的治疗靶点。

Project Summary Fragile X Syndrome (FXS) is the most common type of mental retardation that can be linked to a single gene mutation. FXS patients exhibit many behavioral alterations, as well as abnormal development of synapses in the brain. Astrocytes, the major type of glia in the mammalian brain, regulate synaptic and neuronal functions and are implicated in many developmental and degenerative neurological diseases. The goal of this proposal is to determine the roles of astrocytes in FXS. Combining mouse genetics, live imaging, synaptic molecular profiling, behavioral analyses and pharmacological intervention, we propose 3 aims. In Aim 1, we study how astrocytic deletion of Fragile X Mental Retardation Protein (FMRP) contributes to the synaptic and behavioral defects observed in mice. We will generate transgenic mice in which FMRP is selectively deleted or exclusively expressed in astrocytes. We will then compare the synaptic and behavioral phenotypes of these mice with those of wild-type controls and FMRP full knockout mice. Aim 2 builds upon our earlier observation that astrocyte-specific FMRP knockout mice have increased production of immature dendritic spines of cortical neurons. We will combine in vivo imaging with mathematical modeling and synaptic proteomic imaging to address how astrocytic deletion of FMRP affects the spatial distribution of spinogenesis on excitatory cortical neurons, as well as synaptic/peri-synaptic neuronal and astrocytic protein expression of newly formed spines. In Aim 3, we examine the functional changes of synapses in mice in which FMRP is selectively deleted in astrocytes. In particular, we will examine how glial glutamate uptake and synaptic glutamate concentration are affected in astrocyte-specific FMRP knockout mice, and determine if correcting abnormal glutamate uptake alleviates the dendritic spine defects in these mice. The proposed work will be the first systematic in vivo study investigating astrocytic contribution to FXS. By examining the role of astrocytes in the neuropathology of FXS, these studies will advance our understanding of the disease and potentially point out new therapeutic targets.