Development of synaptic abnormality in fragile X mice

脆性 X 小鼠突触异常的发展

• 批准号: 8446275
• 负责人: Yi Zuo
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446275
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Affect; Age; Age-Months; Animals; Apical; Astrocytes; Autistic Disorder; 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; Learning Disabilities; Life; Mental Retardation; Microscopy; Molecular; Morphogenesis; Morphology; Motor; Motor Cortex; Mus; Nervous system structure; Neuroglia; Neurons; Pathogenesis; 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; disability; hippocampal pyramidal neuron; improved; in utero; in vivo; learned behavior; motor learning; motor skill learning; mouse model; new therapeutic target; novel; postsynaptic; pyridine; receptor; receptor expression; tissue fixing; two-photon

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.

描述（由申请人提供）：脆性 X 综合征 (FXS) 是遗传性智力迟钝的最常见形式，其特征是成年皮质神经元中存在大量未成熟的突触后树突棘。该项目的目的是在 FXS (Fmr1 KO) 小鼠模型的疾病进展过程中检查不同皮质区域和大脑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。目标 1 系统地检查发育中和成年 Fmr1 KO 小鼠皮质中树突棘形态和动力学的改变。它将直接检验当前的假设，即 FXS 是由脊柱修剪和成熟的发育缺陷引起的。目标 2 将学习障碍的进展与脊柱异常的发展联系起来。它还剖析并比较了 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。目标 3 研究 Fmr1 KO 中皮质神经元树突棘异常发育中神经元和胶质细胞的作用。拟议研究的结果将提供有关小鼠 FXS 发病机制期间脊柱动力学的急需细节。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治疗靶点。