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：
9918160
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/9918160
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 mouse genetics 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.

项目概要 Dystroglycan 是一种高度糖基化的跨膜受体，在多种组织中表达整个发育过程，包括肌肉和大脑。 18 个基因中至少一个的突变会减少肌营养不良聚糖糖基化和功能，导致一组异质性人类先天性肌营养不良症（营养不良症）以肌肉无力、皮质畸形、认知障碍和癫痫发作。在大脑中，神经胶质细胞和神经元高度表达肌营养不良聚糖。虽然肌营养不良聚糖已被广泛研究了其在皮质发育过程中调节径向胶质支架完整性的作用，神经元肌营养不良聚糖的后续功能仍然难以捉摸。最近，一个令人惊讶的需求确定了神经元肌营养不良聚糖在 CCK/CB1R+ 中间神经元突触形成和维持中的作用。然而，对肌营养不良聚糖如何选择性调节形成和形成的详细机制的了解缺乏 CCK/CB1R+ 突触的维护。根据这些发现和我的初步数据，我将测试兴奋性神经元中表达的肌营养不良聚糖促进存活和形成的假设 CCK/CB1R+ 中间神经元及其突触以糖基化依赖性方式。该项目将结合使用以下方法来阐明肌营养不良聚糖如何在抑制性突触中发挥作用：体内遗传模型和体外神经元的组织学、切片电生理学和成像方法文化。目标 1 将检验突触前 CCK/CB1R+ 中间神经元经历程序化细胞的假设在没有突触后肌营养不良聚糖的情况下死亡，以及肌营养不良聚糖是否是初始形成所必需的或维持功能性突触。目标 2 将提供关于肌营养不良聚糖如何促进的机制见解通过定义肌营养不良聚糖介导的突触形成是否需要其抑制性突触发生糖基化。这些实验将为神经元的基本机制提供重要的见解。肌营养不良聚糖控制亚型特异性抑制性突触发育。这项研究还将提供线索肌聚糖病中特定神经系统症状的分子和细胞起源，最终有助于为恢复肌营养不良聚糖糖基化和脑功能的治疗策略的制定提供信息患者。