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

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，很少有潜在的治疗途径来治疗这种疾病。 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。 相关性（参见说明）： 在小鼠模型中研究脆性X综合征的基本病理生理学并检查其发展， 谈话动力学将提供有关治疗这种疾病基本问题的见解。我们将探讨 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将突触E/I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.