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The Journal of Neuroscience, March 15, 2006, 26(11):2841-2851; doi:10.1523/JNEUROSCI.4823-05.2006

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Cellular/Molecular
Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking - and -Dystrobrevin

R. Mark Grady,^1,2 David F. Wozniak,³ Kevin K. Ohlemiller,⁴ and Joshua R. Sanes^2,5

Departments of ¹Pediatrics, ²Anatomy and Neurobiology, ³Psychiatry, and ⁴Otolaryngology, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁵Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138

Correspondence should be addressed to R. Mark Grady, Department of Pediatrics, Washington University School of Medicine, Campus Box 8208, 660 South Euclid Avenue, St. Louis, MO 63110. Email: grady{at}kids.wustl.edu

The dystrobrevins (DB and DB) 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 DB, DB, 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 DB and DB, and DBs are depleted from these synapses in mice lacking dystrophin. In dystrophin mutants and DB,DB 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 DB or DB. 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.

Key words: dystrophin; ERG; GABA receptor; muscular dystrophy; retina; behavior

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Received Aug. 23, 2005; revised Jan. 23, 2006; accepted Jan. 26, 2006.

Correspondence should be addressed to R. Mark Grady, Department of Pediatrics, Washington University School of Medicine, Campus Box 8208, 660 South Euclid Avenue, St. Louis, MO 63110. Email: grady{at}kids.wustl.edu

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