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
• 负责人: Lu Chen
• 金额: $ 66.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9063079
• 关键词: ARHGEF5 gene; Acute; Adult; Affect; Age; Bathing; Behavior; Behavioral; Behavioral Assay; Binding; Biochemical; Brain; CGG repeat expansion; Childhood; Chronic; Clinical Research; DNA Methylation; Defect; Development; Disease; Economics; Electrophysiology (science); Emotional; Environment; Equilibrium; Exhibits; Exposure to; FMR1; Fragile X Syndrome; Functional disorder; G-Protein-Coupled Receptors; Gene Silencing; Genes; Genetic; Goals; Hippocampus (Brain); Human; Hypermethylation; Impairment; Instruction; Intellectual functioning disability; Knock-out; Knockout Mice; Lead; Learning; Link; Longevity; Masks; Mediating; Messenger RNA; Mus; Nature; Neurodevelopmental Disorder; Neurons; Oxytocin; Pathogenesis; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physiological; Property; Protein Biosynthesis; Proteins; RNA-Binding Proteins; Recording of previous events; Research Personnel; Role; SERPINA4 gene; Sensory Process; Shapes; Signal Transduction; Slice; Societies; Staging; Stem cells; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; Tretinoin; age related; autism spectrum disorder; base; cognitive disability; embryonic stem cell; environmental enrichment for laboratory animals; experience; genetic manipulation; insight; mouse model; osmotic minipump; protein expression; protein function; research study; response; sensory stimulus; success; therapeutic target; tool

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. RELEVANCE (See instructions): Studying the basic pathophysiology of fragile X-syndrome in a mouse model and examining its developmen- tal dynamics will provide insight into fundamental questions relevant to treating this disorder. We will explore the influence of activity and behavioral history on subsequent synaptic E/l state and learning capacity to see if activating oxytocin signaling restores the synaptic E/l state to a normal level to support normal learning.

脆弱的X-Syndrome是由FMRI基因的功能失活引起的，代表了最常见的 智障的遗传形式。然而，脆弱的X综合征发病机理的机制是 不完全理解。结果，很少有治疗该疾病的潜在治疗途径。 基于观察到不同形式的突触可塑性，最突出的mglur5依赖性有限公司 和视黄酸依赖性稳态可塑性，在fMRI敲除小鼠中被阻塞，目前的项目 由总体假设领导，即脆弱的X-Syndrome涉及经验驱动的突触的损害 激发/抑制（E/L）调整。在这一假设的指导下，我们提出了四个探索的特定目标 使用条件和 构成fMRI基因失活以及生物学，生理和行为测定的结合， 着重于活动和经验引起的突触兴奋性/抑制（E/L）状态的变化。 此外，我们建议研究激活催产素信号是否可以恢复 FXS小鼠的海马电路中的E/L状态改变。通过这些实验，我们的目标是建立 鼠标模型突触功能障碍，尤其是与突触E/L不平衡相关的突触功能障碍与 FXS中的行为缺陷，并获得对FXS相关的发展的全面理解 病理。这些研究将导致对脆弱X综合征的更好，更全面的了解 并定义可能导致潜在治疗靶标的疾病机制。 相关性（请参阅说明）： 在小鼠模型中研究脆弱X综合征的基本病理生理学并检查其发育媒体 TAL Dynamics将为与治疗这种疾病有关的基本问题提供洞察力。我们将探索 活动和行为历史对随后的突触E/L状态和学习能力的影响 如果激活催产素信号传导将突触E/L状态恢复到正常水平以支持正常学习。