Development of synaptic abnormality in fragile X mice

脆性X综合征(FXS)是最常见的遗传性智力低下形式，其特征是 成年皮质神经元中未成熟突触后树突棘的丰富。这个项目的目标是 是研究大脑不同皮质区域和不同层的脊柱动力学和形态 FXS(Fmr1 KO)小鼠模型的疾病进展，并探索潜在的治疗策略 针对不同的信号通路和细胞类型纠正突触结构和学习行为 缺陷。使用经颅双光子显微镜，结合分子方法进行操作 在活体中单个皮质神经元的基因表达，我们提出了三个目标。目标1系统地检查 发育中和成年Fmr1KO小鼠大脑皮质树突棘形态和动力学的改变。会的 直接测试当前的假设，即FXS是由脊柱修剪和发育缺陷引起的 成熟。目的2剖析和比较两种可能的治疗策略的细胞机制。 FXS。目的3探讨神经元和神经胶质细胞在皮质树突棘异常发育中的作用 Fmr1KO的神经元。拟议研究的结果将提供有关脊柱的迫切需要的细节 FXS在小鼠发病中的动态变化。这些信息将有助于阐明细胞 这种疾病的机制，并可能导致确定新的细胞靶点的治疗。

Fragile X Syndrome (FXS) is the most frequent form of inherited mental retardation, and characterized by an abundance of immature postsynaptic dendritic spines in adult cortical neurons. The objective of this project is to examine spine dynamics and morphology in different cortical regions and layers of the brain during disease progression in a mouse model of FXS (Fmr1 KO), and to explore potential therapeutic strategies targeting different signaling pathways and cell types to correct both synaptic structural and learning behavioral defects. Using transcranial two-photon microscopy, in combination with molecular approaches to manipulate gene expression in individual cortical neurons in vivo, we propose 3 aims. Aim 1 systematically examines altered dendritic spine morphology and dynamics in the cortex of developing and adult Fmr1 KO mice. It will directly test the current hypothesis that FXS results from a developmental defect in spine pruning and maturation. Aim 2 dissects and compares the cellular mechanisms of two potential therapeutic strategies for FXS. Aim 3 investigates neuronal and glial roles in abnormal development of the dendritic spine of cortical neurons in Fmr1 KOs. Results from the proposed studies will provide much needed details about spine dynamism during the pathogenesis of FXS in mice. Such information will help to elucidate the cellular mechanisms for this disease and potentially lead to identification of new cellular targets for treatment.