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.