Mechanism of dystroglycan function at inhibitory synapses.

点击翻译按钮获取中文摘要

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.