The Role of Dystrophin in Synapse Development

Project Summary (Abstract): Duchenne muscular dystrophy (DMD), the most common form of childhood muscular dystrophy, is caused by mutations in the gene encoding the protein dystrophin. In addition to debilitating muscle degeneration, patients display a range of cognitive deficits and comorbidities with neurodevelopmental disorders thought to result

from loss of dystrophin normally expressed in the brain. While the function of dystrophin in muscle tissue has been well characterized, its role in the brain is still poorly understood. The highest expression of dystrophin in the brain is in cerebellar Purkinje cells (PC), where it colocalizes with postsynaptic GABAA receptor clusters.

Dystrophin is a member of the dystrophin glycoprotein complex (DGC), a large transmembrane protein complex thought to act as a transsynaptic signaling/adhesion molecule through binding to presynaptic neurexin or neurexin-like proteins. Mice lacking expression of dystrophin show a severe (~40-60%) reduction in the

number of inhibitory synaptic connections, suggesting dystrophin and the DGC are necessary for inhibitory synapse formation or maintenance. However, the role of the DGC in these processes has not been determined. We hypothesize that dystrophin and the DGC are critical for maturation of inhibitory synapses during development. Our preliminary data suggests that in the absence of dystrophin expression,

inhibitory synapses on PC remain in an immature state into late development. We find that a wide range of anatomical and functional measures of synapses function remain at immature levels in dystrophin-deficient PCs. Understanding basic mechanisms of inhibitory synapse maturation will be critical to understanding

neurodevelopmental disorders arising from impaired synaptic development. Understanding the function of dystrophin and the DGC at inhibitory synapses will provide critical guidance for developing future treatments and therapies for DMD symptoms related to brain function. We will investigate the role of dystrophin and the

DGC in inhibitory synapses maturation in the following three aims: Aim 1: Determine the role of dystrophin and the DGC in inhibitory synapse maturation. Hypothesis: Inhibitory synapses remain in an immature state in dystrophin-deficient PCs. Aim 2: Determine the timing of dystrophin function in synapse development.

Hypothesis: Dystrophin and the DGC have unique roles at developing and mature synapses. Aim 3: Determine if enhancing GABAAR currents rescues synapse maturation. Hypothesis: Enhancing GABAAR function will rescue inhibitory synapse maturation in dystrophin-deficient PCs.