Molecular regulation of experience-dependent synapse and dendrite stabilization

描述（由申请人提供）：发育期间神经元回路的正确布线导致建立作为学习、记忆和认知基础的高效网络。越来越清楚的是，许多神经系统疾病，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布线中的作用是产生治疗这些疾病的疗法和治疗方法的第一步。这项提议将研究一个基因cpg15是如何参与这一过程的。具体来说，它将测试cpg15是否需要在发育中的cpg15基因敲除小鼠的视觉皮层的神经元回路形成过程中的突触和树突的活性依赖性稳定。存在大量文献记录小鼠视觉系统的发育，使其成为电路形成的有用模型。将使用电生理学检查突触和树突稳定性的缺陷，以测量突触功能的参数。在记录过程中，神经元将充满小的可扩散分子，生物细胞素，允许以后重建和分析其树突状乔木。在发育中的cpg15基因敲除小鼠中，通过进行单眼剥夺来评估回路可塑性，这是一种有效连接的测定，单眼剥夺是一种操纵感觉体验以诱导视觉系统连接变化的经典方法。这些变化将通过光学固有信号成像来测定，以测量单眼剥夺后对剥夺和睁开眼睛的皮质反应性。该提案还将测试使用慢病毒介导的基因转移拯救cpg15表达是否足以拯救cpg15敲除小鼠中缺乏经验依赖性可塑性和突触和乔木稳定性缺陷。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布线缺陷的治疗潜力。许多神经系统疾病，包括自闭症，可能是由大脑回路的异常布线引起的。识别参与大脑发育的基因，如cpg15基因，并了解它们如何工作，是开发有效治疗这些疾病的关键。

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.