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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：
9237067
负责人：
Yi Zuo
金额：
$ 47.61万
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/9237067
关键词：
Address Adolescent Adolescent Development Adult Affect Array tomography Astrocytes Autistic Disorder Behavioral Behavioral Genetics 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 Life Link Mental Retardation Messenger RNA Metals Molecular Molecular Profiling Morphology Motor Cortex Mus Neurodegenerative Disorders Neuroglia Neurologic Neurons Pathogenesis Patients Phenotype Production Proteins Proteomics Research Role Sensory Process 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 learning 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.

项目总结