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Delineating the synapse coordination pathway

描绘突触协调通路

基本信息

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
项目类别：
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

项目摘要

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.

项目总结