Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking α- and β-Dystrobrevin

Abstract

The dystrobrevins (αDB and βDB) bind directly to dystrophin and are components of a transmembrane dystrophin–glycoprotein complex (DGC) that links the cytoskeleton to extracellular proteins in many tissues. We show here that αDB, βDB, and dystrophin are all concentrated at a discrete subset of inhibitory synapses on the somata and dendrites of cerebellar Purkinje cells. Dystrophin is depleted from these synapses in mice lacking both αDB and βDB, and DBs are depleted from these synapses in mice lacking dystrophin. In dystrophin mutants and αDB,βDB double mutants, the size and number of GABA receptor clusters are decreased at cerebellar inhibitory synapses, and sensorimotor behaviors that reflect cerebellar function are perturbed. Synaptic and behavioral abnormalities are minimal in mice lacking either αDB or βDB. Together, our results show that the DGC is required for proper maturation and function of a subset of inhibitory synapses, that DB is a key component of this DGC, and that interference with this DGC leads to behavioral abnormalities. We suggest that motor deficits in muscular dystrophy patients, which are their cardinal symptoms, may reflect not only peripheral derangements but also CNS defects.