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
- 来源:
- 关键词:ARHGEF5 geneAcuteAdultAgeBathingBehaviorBehavioralBehavioral AssayBiochemicalBrainChronicClinical TrialsDefectDevelopmentDiseaseEquilibriumFragile X Mental Retardation ProteinFragile X SyndromeFunctional disorderGene SilencingGenesGeneticGoalsHippocampus (Brain)HumanImpairmentIntellectual functioning disabilityKnockout MiceLeadLearningLinkMasksMental RetardationMusMutationNatureNeurodevelopmental DisorderNeurotransmitter ReceptorOxytocinPathogenesisPathologyPathway interactionsPhysiologicalPropertyProtein BiosynthesisReceptor SignalingRecording of previous eventsRoleSensory ProcessShapesSignal TransductionSliceStagingSynapsesSynaptic TransmissionSynaptic plasticityTestingTherapeuticTretinoinage relatedautism spectrum disorderbaseenvironmental enrichment for laboratory animalsexperienceinsightmouse modelneurodevelopmentneurotransmissionosmotic minipumpprotein functionresearch studyresponsesensory stimulussuccesssynaptic functiontherapeutic target
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lu Chen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:
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:
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
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8300819 - 财政年份:2011
- 资助金额:
$ 68.87万 - 项目类别:
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