MOLECULAR BIOLOGY OF SYNAPTIC GROWTH AND PLASTICITY

突触生长和可塑性的分子生物学

• 批准号: 6392685
• 负责人: Ehud Isacoff
• 金额: $ 37.03万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392685
• 关键词: Drosophilidae; fluorescent dye /probe; gene targeting; molecular cloning; neural plasticity; neurogenetics; neurophysiology; potassium channel; synaptogenesis

DESCRIPTION (Adapted from applicant's abstract): Two mechanisms (one activity-dependent, and the other activity-independent) are thought to regulate synaptic size and strength, and to function in parallel to expand the nerve terminal and its output to match the size of its target. Both mechanisms are proposed to depend on back and forth signaling between the pre- and postsynaptic cells. This study aims to identify new proteins that control synaptic growth, and to ask fundamental questions about the relationship between the structural and functional development of the synapse: How does the postsynaptic cell signal its size and activity to the presynaptic cell? By what means does the presynaptic cell respond? What is the relation between the growth of new synaptic release sites and the establishment of their function? Does development include the long-term modulation of transmission efficacy at release sites, as has been proposed to explain plasticity in adult? These studies will focus on a model genetic system, the glutamatergic neuromuscular synapse in the fruitfully Drosophila. The compelling reasons to use this system are the ability to conduct mutant screens, the ease of making transgenic animals, and the ready accessibility of the organism at many developmental stages to microscopic and physiological study. We will develop new protein-based optical reporters that will to visualize synaptic morphology, synaptic activity and the assembly of the protein signaling of the synapse. Transgenic methods will be used to generate stable lines of animals expressing these optical reporters in appropriate cells. These reporters will be used to follow synapse development with non-invasive time-lapse imaging, enabling us to elucidate the relationship between synapse formation and functional signaling in wild- type animals, as well as in mutants of synapse formation. The reporter expressing animals will also be used in large-scale mutant screens for new genes that control synaptic growth. The genes identified in the screen will be cloned, molecularly described, and placed into pre- and postsynaptic molecular signaling pathways. Synaptic growth genes discovered in Drosophila are likely to be highly conserved, allowing us to discover the I fundamental molecular machinery of synaptic growth in the human brain.

描述（改编自申请人的摘要）：两种机制（一种 活动依赖性和其他活动无关）被认为是调节 突触的大小和强度，并平行发挥作用，以扩大神经 终端及其输出匹配其目标的大小。这两种机制都是 建议依赖于前和后之间的来回信令， 突触后细胞这项研究的目的是确定新的蛋白质， 突触的生长，并提出一些基本问题， 突触的结构和功能发展之间的关系： 突触后细胞将其大小和活动信号传递给突触前细胞？仗着什么 意味着突触前细胞有反应吗这是什么关系 新突触释放位点的生长及其功能的建立？ 发展是否包括传播功效的长期调节 释放的网站，已被提出来解释可塑性在成人？这些 研究将集中在一个模型遗传系统，神经肌肉 果蝇中的突触使用该系统的令人信服的理由 是进行突变筛选的能力， 动物，以及生物体在许多发育阶段的可接近性 阶段到显微镜和生理学研究。发展新型 基于蛋白质的光学报告分子，将可视化突触形态， 突触活动和突触的蛋白质信号传导的组装。 转基因方法将用于产生稳定的动物品系， 将这些光学报告子放入适当的细胞中。这些记者将习惯于 用非侵入性的延时成像来跟踪突触的发育，使我们能够 阐明突触形成和功能信号之间的关系 在野生型动物以及突触形成的突变体中。记者 表达动物也将用于大规模的突变筛选， 控制突触生长的基因在筛选中识别的基因将是 克隆，分子描述，并放置到突触前和突触后分子 信号通路在果蝇中发现的突触生长基因很可能 是高度保守的，让我们能够发现 人类大脑中突触生长的机制。