Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy.
The dystrophin-associated protein complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.
Sillitoe
Roy V
RV
Department of Cell Biology and Anatomy, and Genes and Development Research Group, Faculty of Medicine, The University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Benson
Matthew A
MA
Blake
Derek J
DJ
Hawkes
Richard
R
D000818:Animals; D015153:Blotting, Western; D064032:Calbindin 2; D002352:Carrier Proteins / Q000096:biosynthesis*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000074765:Dysbindin; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics; D049029:Dystrophin-Associated Proteins; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology*; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis; D013569:Synapses / Q000378:metabolism* / Q000473:pathology*
D064032:Calbindin 2; D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins; D064030:S100 Calcium Binding Protein G; C071871:zebrin II; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D002795:Choline O-Acetyltransferase