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

脆性X综合征是由fMRI基因功能失活引起的，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。 根据观察，不同形式的突触可塑性，最显著的是mGluR5依赖的LTD 和视黄酸依赖的动态平衡可塑性，在fMRI基因敲除小鼠中被阻断，本项目 是由脆性X综合征涉及经验驱动的突触受损这一总体假设引起的 兴奋/抑制(E/L)调节。在这一假设的指导下，我们提出了四个具体的目标，以探索 用条件性和非条件性方法研究FXS小鼠模型发病的本质和发展动力学 结构性功能核磁共振基因失活和生化、生理和行为分析的组合， 重点放在活动和经验诱导的突触兴奋/抑制状态(E/L)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小鼠海马区E/L状态的改变通过这些实验，我们的目标是在一个 小鼠模型突触功能障碍，特别是与突触E/L失衡有关的功能障碍如何与 FXS的行为缺陷，并对FXS相关的发展有一个全面的了解 病理学。这些研究将有助于更好、更全面地了解脆性X综合征 并确定可能导致确定潜在治疗靶点的疾病机制。 相关性(请参阅说明)： 通过建立小鼠脆性X综合征模型，研究脆性X综合征的基本病理生理学，并探讨其发生发展规律。 TAL动力学将提供对与治疗这种疾病相关的基本问题的洞察。我们将探索 活动和行为史对后继突触E/L状态和看学习能力的影响 如果激活催产素，信号会将突触的E/L状态恢复到正常水平，以支持正常学习。

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.