Contribution of astrocytes to the Fragile X Syndrome

星形胶质细胞对脆性 X 综合征的影响

• 批准号: 9349581
• 负责人: Yi Zuo
• 金额: $ 44.82万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-08 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349581
• 关键词: Address; Adolescent; Adolescent Development; Adult; Affect; Array tomography; Astrocytes; Autistic Disorder; Behavioral; Brain; Brain imaging; Cells; Data; Defect; Dendrites; Dendritic Spines; Development; Disease; Electrophysiology (science); Etiology; Exhibits; FMR1; Fragile X Syndrome; Gene Mutation; Gene Silencing; Genetic; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; Goals; Image; Imaging Techniques; Impairment; In Vitro; Inherited; Intervention; Knock-out; Knockout Mice; Learning; Link; Mental Retardation; Messenger RNA; Metals; Molecular; Molecular Profiling; Morphology; Motor Cortex; Mus; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Pathogenesis; Patients; Pharmacology; Phenotype; Production; Proteins; Proteomics; Research; Role; Sensory; Slice; Social Behavior; Spatial Distribution; Synapses; Testing; Transgenic Mice; Vertebral column; Wild Type Mouse; Work; behavioral impairment; density; hippocampal pyramidal neuron; in vivo; in vivo imaging; learned behavior; mRNA Expression; mathematical model; motor learning; motor skill learning; neuropathology; new therapeutic target; prevent; protein expression; protein profiling; public health relevance; repetitive behavior; reuptake; social; synaptic function; synaptogenesis; uptake

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.

项目概要 脆性 X 综合征 (FXS) 是最常见的精神发育迟滞类型，可能与单一因素有关 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大脑中神经胶质细胞的主要类型，调节突触和 神经元功能，并与许多发育性和退行性神经系统疾病有关。这 该提案的目标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、 突触分子分析、行为分析和药理学干预，我们提出了 3 个目标。瞄准 1，我们研究星形细胞缺失脆性 X 智力迟钝蛋白（FMRP）如何促进突触 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小鼠和 FMRP 全敲除小鼠的比较。目标 2 建立在我们之前的基础上 观察到星形胶质细胞特异性 FMRP 敲除小鼠未成熟树突的产生增加 皮层神经元的棘。我们将体内成像与数学建模和突触相结合 蛋白质组成像解决星形胶质细胞 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细胞蛋白表达的影响 新形成的刺。在目标 3 中，我们检查了 FMRP 作用下小鼠突触的功能变化。 星形胶质细胞中选择性删除。特别是，我们将研究神经胶质细胞谷氨酸的摄取和突触如何 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 异常的谷氨酸摄取减轻了这些小鼠的树突棘缺陷。拟议的工作将是 第一个系统体内研究调查星形胶质细胞对 FXS 的贡献。通过检查星形胶质细胞的作用 FXS 的神经病理学，这些研究将增进我们对这种疾病的理解，并可能指出 找出新的治疗靶点。