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.

项目概要 所有的大脑功能，从感觉知觉到行为，都源自突触的模式和特性 数十亿个单个神经元之间发现了连接。这些突触有多种形式，但有两种 存在的主要类别：电突触和化学突触。虽然这些类别被认为是不同的 生化单位，很明显这两种类型的发展是相互联系的。例如，电力中断 突触改变化学突触发育，导致各种行为缺陷，同时扰乱 化学突触影响电突触的形式和功能。该领域的障碍仍然存在 了解神经元如何协调这些不同突触类型的发育。引人注目、新兴 有证据表明，这种突触协调可以通过协调一致的调节途径来实现。我们的 工作确定了与自闭症和癫痫相关的基因 Neurobeachin 是电气和化学所需的 通过结合两种类型突触的细胞内支架来形成突触，这是形成突触所必需的 构建功能性突触。此外，我们的初步工作表明 Neurobeachin 的破坏- 相互作用的分子也会导致电突触和化学突触形成的缺陷。这些作品的 证据开始建立一个模型，其中突触协调是通过调节途径实现的 对于两种突触类型都是必需的。然而，在理解遗传的全部范围方面仍然存在一个关键差距 构成突触协调通路的调节网络。因此，该项目的目标是 使用遗传方法识别体内调节电和化学突触协调的基因 可访问的脊椎动物模型系统。该提案使用斑马鱼莫特纳电路及其定型 电和化学突触以及无与伦比的遗传和成像可访问性来评估突触 脊椎动物体内的协调。在 Aim1 中，我们建议识别协调电的候选基因 使用我们高效的 CRISPR 筛选流程进行化学突触形成。在 Aim2 中，我们检查 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的新前沿，即协调的途径 电和化学突触的发育。