MOLECULAR BIOLOGY OF SYNAPTIC GROWTH AND PLASTICITY

突触生长和可塑性的分子生物学

• 批准号: 6650177
• 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/6650177
• 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)：两个机构(一个 依赖于活动，其他依赖于活动)被认为是调节 突触的大小和强度，以及平行扩张神经的功能 终端及其输出以匹配其目标的大小。这两种机制都是 建议依赖于Pre和Pre之间的来回信令 突触后细胞。这项研究的目的是识别新的控制蛋白质 突触生长，并询问有关关系的基本问题 突触的结构和功能发展之间：突触是如何 突触后细胞将其大小和活动信号传递给突触前细胞？凭什么？ 意味着突触前细胞有反应吗？两者之间的关系是什么？ 新的突触释放部位的生长及其功能的建立？ 发展是否包括对传播效能的长期调制 释放部位，已经被提出用来解释成人的可塑性？这些 研究将集中在一个模型遗传系统，谷氨酸能神经肌肉 果蝇体内的突触。使用该系统的令人信服的理由 是进行突变筛选的能力，制造转基因的简便性 动物，以及有机体在许多发育阶段的现成可获得性 进入显微和生理研究阶段。我们将开发新的 基于蛋白质的光学记者将可视化突触形态， 突触活性与突触信号蛋白的组装。 转基因方法将被用来产生稳定的表达动物品系 这些光学记者被关在适当的牢房里。这些记者将习惯于 通过非侵入性时间推移成像跟踪突触发育，使我们能够 阐明突触形成与功能信号的关系 在野生型动物中，以及突触形成的突变体中。这位记者 表达动物也将用于新的大规模突变筛选 控制突触生长的基因。屏幕上识别的基因将是 克隆，分子描述，并放入突触前和突触后分子中 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，使我们能够发现I基本分子 人脑中突触生长的机制。