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，可与单个 基因突变。FXS患者表现出许多行为改变，以及 大脑中的突触。星形胶质细胞是哺乳动物大脑中的主要胶质细胞类型，它调节突触和 神经功能，并与许多发育和退行性神经疾病有关。这个 本研究的目的是确定星形胶质细胞在FXS中的作用。结合了小鼠遗传学，活体成像， 突触分子图谱、行为分析和药物干预，我们提出了三个目标。在AIM 1，我们研究了星形细胞缺失脆性X智力低下蛋白(FMRP)对突触的作用 以及在老鼠身上观察到的行为缺陷。我们将产生转基因小鼠，在其中FMRP被选择性地 在星形胶质细胞中被删除或独占表达。然后我们将比较突触和行为表型 与野生型对照组和FMRP全基因敲除小鼠进行比较。Aim 2是在我们之前的基础上建立的 星形胶质细胞特异性FMRP基因敲除小鼠增加未成熟树突状细胞的产生 大脑皮层神经元的脊椎。我们将把活体成像与数学建模和突触相结合 蛋白质组学成像研究星形细胞FMRP缺失如何影响脊柱发生的空间分布 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的表达 新形成的脊椎。在目标3中，我们检测了FMRP所致小鼠突触的功能变化。 在星形胶质细胞中选择性删除。特别是，我们将研究神经胶质谷氨酸摄取和突触 星形胶质细胞特异性FMRP基因敲除小鼠的谷氨酸浓度受到影响，并决定是否纠正 异常摄取谷氨酸可减轻这些小鼠的树突状棘突缺陷。拟议的工作将是 首次系统的体内研究，探讨星形细胞对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该疾病的理解和潜在的 寻找新的治疗靶点。

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.