Development of synaptic abnormality in fragile X mice

脆性 X 小鼠突触异常的发展

• 批准号: 8275856
• 负责人: Yi Zuo
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8275856
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Affect; Age-Months; Animals; Apical; Astrocytes; Autistic Disorder; Behavior; Behavior Therapy; Behavioral; Brain; Brain imaging; Cells; Coculture Techniques; Data; Defect; Dendrites; Dendritic Spines; Development; Disease; Disease Progression; Electroporation; Environment; Excitatory Synapse; Exhibits; FMR1 Gene; FMRP; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression; Genes; Image; Impairment; Individual; Inherited; Investigation; Isoxazoles; Knock-out; Label; Lead; Learning; Life; Mental Retardation; Microscopy; Molecular; Morphogenesis; Morphology; Motor; Motor Cortex; Mus; Nervous system structure; Neuroglia; Neurons; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Population; Propionic Acids; Proteins; Psyche structure; Role; Signal Pathway; Signal Transduction; Structure; Synapses; System; Testing; Therapeutic; Time; Vertebral column; X Chromosome; base; cell type; cellular targeting; density; hippocampal pyramidal neuron; in utero; in vivo; motor skill learning; mouse model; new therapeutic target; novel; postsynaptic; public health relevance; pyridine; receptor; receptor expression; tissue fixing; two-photon

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.

脆性X综合征（FXS）是遗传性智力低下的最常见形式，其特征在于 成年皮层神经元中大量未成熟的突触后树突棘。本项目的目标 是检查脊柱动力学和形态学在不同的皮质区域和层的大脑， FXS（Fmr1 KO）小鼠模型中的疾病进展，并探索潜在的治疗策略 靶向不同的信号通路和细胞类型，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， 基因表达的个体皮质神经元在体内，我们提出了3个目标。目标1系统地审查 改变了发育和成年Fmr1基因敲除小鼠皮质中树突棘的形态和动力学。它将 直接检验目前的假设，即FXS是由脊柱修剪的发育缺陷引起的， 成熟目的2剖析和比较两种潜在的治疗策略的细胞机制， FXS。目的3探讨神经元和胶质细胞在皮层树突棘异常发育中的作用 Fmr 1科斯神经元。拟议研究的结果将提供有关脊柱的急需的详细信息 在小鼠FXS发病过程中的动力学。这些信息将有助于阐明细胞的 这种疾病的机制，并可能导致识别新的治疗细胞靶点。