Development of synaptic abnormality in fragile X mice

描述（由申请人提供）：脆性X综合征（Fragile X Syndrome， FXS）是遗传性智力低下的最常见形式，其特征是成人皮质神经元中存在大量未成熟的突触后树突状棘。本项目的目的是研究FXS （Fmr1 KO）小鼠模型疾病进展过程中不同皮质区域和脑层的脊柱动力学和形态学，并探索针对不同信号通路和细胞类型的潜在治疗策略，以纠正突触结构和学习行为缺陷。利用经颅双光子显微镜，结合分子方法来操纵体内单个皮质神经元的基因表达，我们提出了3个目标。目的1系统地检查发育和成年Fmr1 KO小鼠皮层树突棘形态和动力学的改变。这将直接验证目前的假设，即FXS是由脊柱修剪和成熟过程中的发育缺陷引起的。目的2将学习障碍的进展与脊柱异常的发展联系起来。它还剖析和比较了FXS的两种潜在治疗策略对突触结构/功能和学习行为的影响。目的3研究神经元和胶质在Fmr1 ko皮层神经元树突棘异常发育中的作用。本研究的结果将提供小鼠FXS发病过程中脊柱动力学的详细信息。这些信息将有助于阐明这种疾病的细胞机制，并可能导致确定新的细胞治疗靶点。

DESCRIPTION (provided by applicant): 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 correlates the progression of learning disability with the development of spine abnormality. It also dissects and compares the effect of two potential therapeutic strategies for FXS on synaptic structural/function and learning behavior. 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.