Developmental Pathophysiology of Synapses in a Mouse Model of Fragile X Syndrome

脆性 X 综合征小鼠模型突触的发育病理生理学

基本信息

  • 批准号:
    8921625
  • 负责人:
  • 金额:
    $ 68.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-22 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

Fragile X-syndrome is caused by functional inactivation ofthe Fmri gene, and represents the most common genetic form of intellectual disability. However, the mechanisms of fragile X-syndrome pathogenesis are incompletely understood. As a result, few potential therapeutic avenues to treat the disorder are available. Based on observations that different forms of synaptic plasticity, most prominently mGluR5-dependent LTD and retinoic acid-dependent homeostatic plasticity, are blocked in Fmri knockout mice, the present project is led by the overall hypothesis that fragile X-syndrome involves an impairment of experience-driven synaptic excitation/inhibition (E/l) adjustments. Guided by this hypothesis, we propose four specific aims that explore the nature and developmental dynamics of FXS pathogenesis in mouse models using conditional and constitutive Fmri gene inactivation and a combination of biochemical, physiological, and behavioral assays, with a focus on activity- and experience-induced changes in the synaptic excitatory/inhibitory (E/l) state. Additionally, we propose to investigate whether activating oxytocin signaling can restore aspects ofthe altered E/l state in the hippocampal circuitry of FXS mice. With these experiments, we aim to establish in a mouse model how synaptic dysfunction, especially that related to synaptic E/l imbalance, is linked to the behavioral defects in FXS, and to obtain a comprehensive understanding ofthe development of FXS-related pathology. These studies will lead to a better and more comprehensive understanding of fragile X-syndrome and define disease mechanisms that could lead to the identification of potential therapeutic targets.
脆性X综合征是由功能性磁共振成像基因失活引起的,是最常见的 遗传性智力残疾。然而,脆性X综合征的发病机制是 不完全理解。因此,治疗这种疾病的潜在治疗途径很少。 基于不同形式的突触可塑性,最显著的是mGluR 5依赖性LTD 和视黄酸依赖的稳态可塑性,在功能磁共振成像敲除小鼠中被阻断, 脆性X综合征涉及经验驱动的突触损伤, 兴奋/抑制(E/I)调节。在这个假设的指导下,我们提出了四个具体的目标,探索 使用条件性和非条件性方法, 组成型FMRI基因失活和生化、生理和行为测定的组合, 重点在于突触兴奋/抑制(E/I)状态中的活动和经验诱导的变化。 此外,我们建议研究激活催产素信号是否可以恢复某些方面的功能。 FXS小鼠海马电路中改变的E/I状态。通过这些实验,我们的目标是建立一个 小鼠模型如何突触功能障碍,特别是与突触E/I不平衡有关的突触功能障碍, 行为缺陷的FXS,并获得全面的了解FXS相关的发展 病理这些研究将导致对脆性X综合征更好和更全面的了解 并确定疾病机制,从而确定潜在的治疗靶点。

项目成果

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Lu Chen其他文献

Lu Chen的其他文献

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{{ truncateString('Lu Chen', 18)}}的其他基金

Telomerase RNP Prisonbreaks from Phase-Separated Nuclear Body
端粒酶 RNP 从相分离核体中越狱
  • 批准号:
    10714880
  • 财政年份:
    2023
  • 资助金额:
    $ 68.87万
  • 项目类别:
A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity
视黄酸依赖性稳态突触可塑性的分子研究
  • 批准号:
    10841345
  • 财政年份:
    2023
  • 资助金额:
    $ 68.87万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10678938
  • 财政年份:
    2020
  • 资助金额:
    $ 68.87万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10443848
  • 财政年份:
    2020
  • 资助金额:
    $ 68.87万
  • 项目类别:
A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity
视黄酸依赖性稳态突触可塑性的分子研究
  • 批准号:
    10613502
  • 财政年份:
    2020
  • 资助金额:
    $ 68.87万
  • 项目类别:
A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity
视黄酸依赖性稳态突触可塑性的分子研究
  • 批准号:
    10394759
  • 财政年份:
    2020
  • 资助金额:
    $ 68.87万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10271308
  • 财政年份:
    2020
  • 资助金额:
    $ 68.87万
  • 项目类别:
Role of synaptotagmins and neurexin ligands in homeostatic synaptic plasticity
突触结合蛋白和神经毒素配体在稳态突触可塑性中的作用
  • 批准号:
    8854550
  • 财政年份:
    2015
  • 资助金额:
    $ 68.87万
  • 项目类别:
Developmental Pathophysiology of Synapses in a Mouse Model of Fragile X Syndrome
脆性 X 综合征小鼠模型突触的发育病理生理学
  • 批准号:
    9063079
  • 财政年份:
    2014
  • 资助金额:
    $ 68.87万
  • 项目类别:
Large-Scale Molecular Interrogation of Synaptic Transmission
突触传递的大规模分子研究
  • 批准号:
    8300819
  • 财政年份:
    2011
  • 资助金额:
    $ 68.87万
  • 项目类别:

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