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Mechanism of dystroglycan function at inhibitory synapses.

肌营养不良聚糖在抑制性突触中发挥作用的机制。

基本信息

批准号：
9757633
负责人：
Daniel Scott Miller
金额：
$ 4.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757633
关键词：
Apoptosis Apoptotic Binding Biological Assay Biology Brain CNR1 gene Cell Adhesion Molecules Cessation of life Characteristics Cholecystokinin Cortical Malformation Data Development Disease Dystroglycan Electrophysiology (science)Failure Genes Genetic Genetic Models Hippocampus (Brain)Histologic Human Imaging technology Impaired cognition Impairment In Vitro Inhibitory Synapse Institutes Instruction Interneurons Ligands Maintenance Mediating Methods Mission Molecular Mus Muscle Muscle Weakness Mutation National Institute of Neurological Disorders and Stroke Neuroglia Neurologic Neurologic Dysfunctions Neurologic Symptoms Neurons Patients Physiology Presynaptic Terminals Productivity Radial Research Resources Role Seizures Signal Transduction Slice Synapses Testing Tissues Training base career congenital muscular dystrophy dystroglycanopathy effective therapy excitatory neuron experimental study extracellular glycosylation high resolution imaging imaging approach improved in vivo innovation insight neural circuit neurogenetics novel postnatal postsynaptic postsynaptic neurons presynaptic protein function receptor scaffold synaptogenesis targeted treatment therapeutic development tool

项目摘要

Project Summary Dystroglycan is a heavily glycosylated transmembrane receptor expressed in a wide variety of tissues throughout development, including muscle and brain. Mutations in at least one of 18 genes reduce dystroglycan glycosylation and function, causing a heterogeneous group of human congenital muscular dystrophies (dystroglycanopathies) characterized by muscle weakness, cortical malformations, cognitive impairments, and seizures. Within the brain, dystroglycan is highly expressed by glia and neurons. While dystroglycan has been studied extensively for its role in regulating the integrity of the radial glial scaffold during cortical development, the subsequent function of neuronal dystroglycan has remained elusive. Recently, a surprising requirement for neuronal dystroglycan in the formation and maintenance of CCK/CB1R+ interneuron synapses was identified. However, a detailed mechanistic understanding of how dystroglycan selectively regulates the formation and maintenance of CCK/CB1R+ synapses is lacking. Based on these findings and my preliminary data, I will test the hypothesis that dystroglycan expressed in excitatory neurons promotes survival and formation of CCK/CB1R+ interneurons and their synapses in a glycosylation-dependent manner. This project will elucidate how dystroglycan functions at inhibitory synapses using a combination of histological, slice electrophysiology, and imaging approaches in both in vivo genetic models and in vitro neuronal cultures. Aim 1 will test the hypothesis that presynaptic CCK/CB1R+ interneurons undergo programmed cell death in the absence of postsynaptic dystroglycan, and whether dystroglycan is required for the initial formation or maintenance of functional synapses. Aim 2 will provide mechanistic insight into how dystroglycan promotes inhibitory synaptogenesis by defining whether dystroglycan-mediated synapse formation requires its glycosylation. These experiments will provide critical insight into the basic mechanisms by which neuronal dystroglycan controls subtype-specific inhibitory synapse development. This study will also provide clues about the molecular and cellular origins of specific neurological symptoms in dystroglycanopathy, ultimately helping to inform development of therapeutic strategies for restoring dystroglycan glycosylation and brain function in patients.

项目总结