Molecular regulation of experience-dependent synapse and dendrite stabilization

经验依赖性突触和树突稳定的分子调节

• 批准号: 7991786
• 负责人: Jennifer Helen Leslie
• 金额: $ 4.14万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991786
• 关键词: Action Potentials; Affect; Area; Autistic Disorder; Biological Assay; Bolus Infusion; Brain; Cells; Characteristics; Cognition; Defect; Dendrites; Development; Disease; Electrophysiology (science); Etiology; Extracellular Protein; Eye; Frequencies; Gene Transfer; Genes; Genetic; Goals; Growth; Height; Hippocampus (Brain); Image; Infection; Injection of therapeutic agent; Knockout Mice; Learning; Light; Literature; Measurement; Measures; Mediating; Memory; Methods; Modeling; Modification; Molecular; Molecular Genetics; Mus; Neurons; Ocular Dominance; Optics; Play; Process; Proteins; Rattus; Recombinants; Regulation; Relative (related person); Role; Seizures; Sensory; Signal Transduction; Site; Structure; Subfamily lentivirinae; Synapses; Testing; Therapeutic; Time; Vertebral column; Vibrissae; Visual; Visual Cortex; Visual system structure; Work; Xenopus; autism spectrum disorder; barrel cortex; biocytin; critical period; dark rearing; dentate gyrus; effective therapy; experience; extracellular; lentiviral-mediated; monocular deprivation; nervous system disorder; neuron development; neuropsychiatry; optical imaging; overexpression; patch clamp; postnatal; reconstruction; response; superior colliculus Corpora quadrigemina; synaptic function; synaptogenesis; vision development

DESCRIPTION (provided by applicant): Proper wiring of neuronal circuits during development leads to the establishment of highly effective networks that underlie learning, memory and cognition. It is becoming clear that many neurological disorders, such as autism spectrum disorders, and potentially some neuropsychiatric diseases may in part be caused by irregular circuit wiring. Identifying and understanding the role that specific genes play in the developmental wiring of neuronal networks is a first step towards generating therapies and treatments to cure such disorders. This proposal will examine how one gene, cpg15, is involved in this process. Specifically, it will test whether cpg15 is required for activity-dependent stabilization of synapses and dendrites during neuronal circuit formation in the developing visual cortex of a cpg15 knockout mouse. Extensive literature exists documenting the development of the visual system in mice making it a useful model for circuit formation. Defects in synaptic and dendritic stabilization will be examined using electrophysiology to measure parameters of synapse function. During recording, neurons will be filled with the small diffusible molecule, biocytin, allowing for later reconstruction and analysis of their dendritic arbors. Circuit plasticity, an assay for effective wiring will be assessed in the developing cpg15 knockout mouse by performing monocular deprivation, a classical method for manipulating sensory experience to induce changes in visual system wiring. These changes will be assayed by optical intrinsic signal imaging to measure cortical responsiveness to the deprived and open eyes after monocular deprivation. This proposal will also test whether rescue of cpg15 expression using lentiviral-mediated gene transfer is sufficient to rescue deficient experience-dependent plasticity and defects in synapse and arbor stabilization in cpg15 knockout mice. Since CPG15 is a secreted, extracellular molecule it may have therapeutic potential for rescuing circuit wiring deficits regardless of their etiology. Many neurological disorders, including autism, may be caused by abnormal wiring of the brain's circuits. Identifying genes involved in the developmental wiring of the brain, such as the gene cpg15, and understanding how they work is key to developing effective treatments to cure these disorders.

描述（由申请人提供）：在发育过程中神经元回路的正确连接可以导致建立学习、记忆和认知的高效网络。越来越清楚的是，许多神经系统疾病，例如自闭症谱系障碍，以及潜在的一些神经精神疾病可能部分是由不规则的电路布线引起的。识别和理解特定基因在神经元网络发育连接中所起的作用是产生治疗此类疾病的疗法和疗法的第一步。该提案将研究一个基因 cpg15 如何参与这一过程。具体来说，它将测试 cpg15 敲除小鼠发育中的视觉皮层中神经元回路形成过程中突触和树突的活动依赖性稳定是否需要 cpg15。大量文献记录了小鼠视觉系统的发育，使其成为回路形成的有用模型。将使用电生理学来测量突触功能参数来检查突触和树突稳定性的缺陷。在记录过程中，神经元将充满小可扩散分子生物胞素，以便稍后重建和分析其树突乔木。电路可塑性是一种有效布线的测定方法，将通过执行单眼剥夺（一种操纵感官体验以诱导视觉系统布线变化的经典方法）在发育中的 cpg15 敲除小鼠中进行评估。这些变化将通过光学内在信号成像进行分析，以测量单眼剥夺后皮质对被剥夺和睁开的眼睛的反应。该提案还将测试使用慢病毒介导的基因转移来挽救 cpg15 表达是否足以挽救 cpg15 敲除小鼠中经验依赖性可塑性的缺陷以及突触和乔木稳定性的缺陷。由于 CPG15 是一种分泌的细胞外分子，因此无论其病因如何，它都可能具有挽救电路接线缺陷的治疗潜力。许多神经系统疾病，包括自闭症，可能是由大脑回路的异常接线引起的。识别参与大脑发育线路的基因（例如基因 cpg15）并了解它们的工作原理是开发治疗这些疾病的有效疗法的关键。