Contribution of astrocytes to the Fragile X Syndrome

星形胶质细胞对脆性 X 综合征的影响

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要脆弱的X综合征（FXS）是最常见的智力低下类型基因突变。 FXS患者表现出许多行为改变，以及异常的发展大脑中的突触。星形胶质细胞是哺乳动物大脑中的主要类型的神经胶质，调节突触和神经元功能，与许多发育和退化性神经系统疾病有关。这该建议的目标是确定星形胶质细胞在FXS中的作用。结合鼠标遗传学，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。目标 1，我们研究脆弱X智力低下蛋白（FMRP）的星形细胞缺失如何有助于突触和在小鼠中观察到的行为缺陷。我们将生成FMRP选择性的转基因小鼠在星形胶质细胞中删除或独家表达。然后，我们将比较突触和行为表型这些小鼠具有野生型对照和FMRP完整敲除小鼠的小鼠。目标2建立在我们之前的观察星形胶质细胞特异性FMRP敲除小鼠的产生不成熟的树突状产生皮质神经元的脊柱。我们将在体内成像与数学建模和突触结合蛋白质组学成像以解决FMRP的星形细胞缺失如何影响旋转生成的空间分布在兴奋性皮质神经元以及突触/突触神经元和星形胶质细胞蛋白表达上新形成的刺。在AIM 3中，我们检查了FMRP为FMRP的小鼠突触的功能变化在星形胶质细胞中有选择地删除。特别是，我们将研究神经胶质谷氨酸的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，并确定是否校正异常的谷氨酸摄取减轻这些小鼠的树突状脊柱缺陷。拟议的工作将是第一个系统的体内研究研究了对FXS的星形细胞贡献。通过检查星形胶质细胞在 FXS的神经病理学，这些研究将提高我们对疾病的理解，并有潜在的观点摆出新的治疗靶标。