Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice)

Dystrophin is selectively localized in the postsynaptic density of neurons in cerebral cortex, hippocampus and cerebellum. Here, we show by double-immunofluorescence staining that dystrophin is extensively colocalized with GABA(A) receptor subunit clusters in these brain regions. To determine the relevance of this observation, we investigated in mdx mice, which provide a model of Duchenne muscular dystrophy, whether the absence of dystrophin affects the synaptic clustering of GABA(A) receptors. A marked reduction in the number of clusters immunoreactive for the alpha 1 and alpha 2 subunits was observed in, respectively, cerebellum and hippocampus of mdx mice, but not in striatum, which is normally devoid of dystrophin. Furthermore, these alterations were not accompanied by a change in gephyrin staining, although gephyrin is colocalized with the majority of GABA(A) receptor clusters in these regions. These results indicate that dystrophin may play an important role in the clustering or stabilization of GABA(A) receptors in a subset of central inhibitory synapses. These deficits may underlie the cognitive impairment seen in Duchenne patients.