Development of synaptic abnormality in fragile X mice

描述(申请人提供)：脆性X综合征(FXS)是最常见的遗传性智力低下形式，其特征是成人皮质神经元中有大量未成熟的突触后树突棘。本项目的目的是在FXS(Fmr1 KO)小鼠模型中研究疾病进展过程中不同皮质区域和大脑各层的脊柱动力学和形态，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。使用经颅双光子显微镜，结合分子方法在活体中操纵单个皮质神经元的基因表达，我们提出了三个目标。目的1系统研究发育期和成年Fmr1KO小鼠大脑皮质树突棘的形态和动态变化。它将直接检验当前的假设，即FXS是由脊柱修剪和成熟过程中的发育缺陷造成的。目的2学习障碍的进展与脊柱畸形的发展相关。并对FXS两种潜在的治疗策略对突触结构/功能和学习行为的影响进行了剖析和比较。目的探讨神经元和神经胶质细胞在Fmr1KOS皮质神经元树突棘异常发育中的作用。拟议的研究结果将提供关于FXS小鼠发病过程中脊柱动力的迫切需要的细节。这些信息将有助于阐明这种疾病的细胞机制，并可能导致识别新的细胞靶点进行治疗。

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.