Delineating the synapse coordination pathway

描绘突触协调通路

• 批准号: 10790827
• 负责人: Adam C Miller
• 金额: $ 40.56万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790827
• 关键词: Affect; Behavior; Behavioral; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Brain; Brain Diseases; CRISPR screen; Candidate Disease Gene; Cell Transplantation; Cells; Cellular biology; Chemical Synapse; Chemicals; Classification; Complex; Coupled; Defect; Development; Disease; Electrical Synapse; Epilepsy; Equilibrium; Etiology; Foundations; Functional disorder; Genes; Genetic; Goals; Human; Image; Individual; Intellectual functioning disability; Link; Mediating; Modality; Modeling; Molecular; Morphology; Mutation; Myopia; Neurites; Neurons; Neurosciences; Pathway interactions; Pattern; Perception; Phenotype; Population; Process; Property; Proteins; Proteomics; Regulatory Pathway; Role; Sensory; Specific qualifier value; Stereotyping; Synapses; Synaptic Transmission; System; Testing; Triage; Vertebrates; Work; Zebrafish; autism spectrum disorder; candidate identification; experimental study; frontier; gap junction channel; gene discovery; gene interaction; genetic architecture; in vivo; model building; mutant; neural; neural circuit; neurogenetics; neuron development; neuronal circuitry; neurotransmitter release; novel; scaffold; synaptogenesis

PROJECT SUMMARY All of brain function, from sensory perception to behavior, is derived from the pattern and properties of synaptic connections found between billions of individual neurons. These synapses are found in diverse forms, but two major classes exist: electrical and chemical synapses. While these classes are thought to be distinct biochemical units, it is clear the development of both types is linked. For example, the disruption of electrical synapses alters chemical synapse development resulting in a variety of behavioral defects, while perturbing chemical synapses impacts electrical synapse form and function. A barrier in the field remains in understanding how neurons coordinate the development of these distinct synapse types. Strikingly, emerging evidence suggests that such synaptic coordination may be achieved by a concerted regulatory pathway. Our work identifies the autism- and epilepsy-linked gene Neurobeachin as required for both electrical and chemical synapse formation by binding the intracellular scaffolds of both types of synapses, which are necessary for building functional synapses. Additionally, our preliminary work reveals that the disruption of Neurobeachin- interacting molecules also results in defects in both electrical and chemical synapse formation. These pieces of evidence begin to build a model wherein synapse coordination is achieved by a regulatory pathway that is essential for both synapse types. Yet, a critical gap remains in understanding the full extent of the genetic regulatory network that constitutes the synapse coordination pathway. Therefore, the goal of this project is to identify the genes that regulate electrical and chemical synapse coordination in vivo using a genetically accessible vertebrate model system. This proposal uses the zebrafish Mauthner circuit with its stereotyped electrical and chemical synapses and unparalleled genetic and imaging accessibility to assess synaptic coordination in vertebrates in vivo. In Aim1 we propose to identify candidate genes that coordinate electrical and chemical synapse formation using our efficient CRISPR screening pipeline. In Aim2 we examine the effects of candidate mutations on the formation and function of electrical and chemical synapses. Together, the proposed studies will identify the genes required to coordinate electrical and chemical synapse formation in vivo. This work has the potential to reveal a novel frontier in neuroscience, a pathway that coordinates electrical and chemical synapse development.

项目摘要 从感觉感知到行为的所有大脑功能都来自突触的模式和特性 发现数十亿个单个神经元之间的联系。这些突触以各种形式发现，但两个 存在主要类别：电气和化学突触。虽然这些课程被认为是独特的 生化单元，很明显，两种类型的发展都链接在一起。例如，电气的破坏 突触改变化学突触的发展，导致各种行为缺陷，同时扰动 化学突触会影响电突触形式和功能。野外的障碍仍然存在 了解神经元如何协调这些独特的突触类型的发展。令人惊讶的是，出现了 证据表明，这种突触协调可以通过一致的调节途径来实现。我们的 工作识别自闭症和癫痫连接的基因神经曲霉的电气和化学 通过结合两种突触的细胞内支架，是突触形成的，这是必需的 构建功能突触。此外，我们的初步工作表明，神经毛学的破坏 - 相互作用的分子还会导致电气和化学突触形成的缺陷。这些 证据开始建立一个模型，其中突触协调是通过监管途径实现的 两种突触类型必不可少的。然而，关键的差距仍然在理解遗传的全部程度 构成突触协调途径的监管网络。因此，这个项目的目标是 鉴定使用遗传学的基因在体内调节电和化学突触配位的基因 可访问的脊椎动物模型系统。该提案使用斑马鱼毛特纳赛车的刻板印象 电气和化学突触以及无与伦比的遗传和成像可访问性评估突触 体内脊椎动物的协调。在AIM1中，我们建议鉴定候选基因以配合电气的基因 并使用我们有效的CRISPR筛选管道形成化学突触。在AIM2中，我们检查了 候选突变对电和化学突触的形成和功能的影响。在一起， 拟议的研究将确定协调电气和化学突触形成所需的基因 体内。这项工作有可能揭示神经科学中的新型边界，这是一种坐标的途径 电和化学突触的发展。