Cerebellar synaptic defects and abnormal motor behavior in mice lacking alpha- and beta-dystrobrevin.
The dystrobrevins (alphaDB and betaDB) 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 alphaDB, betaDB, 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 alphaDB and betaDB, and DBs are depleted from these synapses in mice lacking dystrophin. In dystrophin mutants and alphaDB,betaDB 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 alphaDB or betaDB. 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.
Grady
R Mark
RM
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA. grady@kids.wustl.edu
Wozniak
David F
DF
Ohlemiller
Kevin K
KK
Sanes
Joshua R
JR
D000818:Animals; D001259:Ataxia / Q000235:genetics; D001522:Behavior, Animal; D002531:Cerebellum / Q000503:physiopathology*; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D049029:Dystrophin-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D009469:Neuromuscular Junction / Q000737:chemistry / Q000473:pathology; D016548:Prosencephalon / Q000737:chemistry / Q000473:pathology; D011597:Psychomotor Performance; D011689:Purkinje Cells / Q000737:chemistry / Q000502:physiology*; D011940:Receptor Aggregation; D011963:Receptors, GABA-A / Q000172:deficiency / Q000502:physiology; D012160:Retina / Q000737:chemistry / Q000503:physiopathology / Q000648:ultrastructure; D013569:Synapses / Q000502:physiology
D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D046912:Multiprotein Complexes; D011963:Receptors, GABA-A; C085339:apo-dystrophin 1; C098885:dystrobrevin