PROJECT SUMMARY Dystroglycan is a transmembrane protein that relies on its extensive glycosylation to interact with a number of extracellular proteins. Dystroglycan hypoglycosylation causes a form of congenital muscular dystrophy (dystroglycanopathy) that is frequently accompanied by a wide range of neurological symptoms. On the severe end of the spectrum, patients exhibit hydrocephalus, type II lissencephaly, retinal/cerebellar hypoplasia, and white matter abnormalities. Patients with milder forms of dystroglycanopathy frequently have seizures and cognitive defects even in the absence of obvious brain abnormalities. Mouse models of dystroglycanopathy have provided invaluable mechanistic insight into Dystroglycan’s many functions in the nervous system, as they faithfully recapitulate many of the neurodevelopmental defects seen in human patients. Recently, we and others have shown that Dystroglycan functions cell-autonomously at subsets of inhibitory synapses in the brain, providing a possible explanation into the etiology of neurological dysfunction in dystroglycanopathy. In this proposal, we examine how Dystroglycan regulates inhibitory synapse development and function. The proposed experiments will: 1) Use genetic approaches to dissect the cellular and molecular mechanisms by which Dystroglycan regulates the establishment and maintenance of inhibitory synapses; 2) Determine whether synaptic defects can be rescued, and whether a specific therapeutic window exists; 3) Define the molecular and functional basis of a newly identified interaction between Dystroglycan and the Cntnap proteins at inhibitory synapses in the brain. These experiments will provide insight into Dystroglycan function in the nervous system and lay the foundation for therapeutic interventions to correct neurological defects in dystroglycanopathy.

PROJECT NARRATIVE Loss of functional Dystroglycan leads to a form of congenital muscular dystrophy that is frequently accompanied by a wide range of neurological defects. This proposal will use a range of genetic models to determine how Dystroglycan controls inhibitory synapse development and function, test whether synaptic defects can be rescued, and define the functional relevance of a novel Dystroglycan interaction at synapses. These studies will provide important insights into the function of Dystroglycan in the nervous system and test a translationally-relevant treatment rationale.