Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy

Dystrophin and its autosomal homologue utrophin are coexpressed in muscle c ells, and utrophin is functionally able to replace dystrophin in models of Duchenne muscular dystrophy. In brain, the two proteins are expressed diffe rentially, suggesting distinct functional roles. Dystrophin is associated w ith postsynaptic GABA(A) receptors in hippocampus, cortex and cerebellum, w hereas utrophin is present extrasynaptically, notably in large brainstem ne urons. Here, the regulation of dystrophin and utrophin was investigated in a model of temporal lobe epilepsy. Adult mice were injected unilaterally wi th kainic acid into the dorsal hippocampus to induce loss of pyramidal cell s and hypertrophy of dentate gyrus (DG) granule cells, as described (Suzuki , F., Junier, M.P., Guilhem, D., Sorensen, J.C. & Onteniente, B. (1995) Neu roscience, 64, 665-674.). These morphological changes were associated with an increase in postsynaptic GABA(A)-receptors in the ipsilateral DG, as dem onstrated by a parallel increase in punctate immunoreactivity to GABA(A)-re ceptor alpha2 subunit, gephyrin and dystrophin in the molecular layer. Thus , both dystrophin and gephyrin were involved in postsynaptic clustering of GABA(A) receptors. A transient induction of utrophin was seen at the onset of degeneration in CA1 and CA3 pyramidal cells and in the hilus. Most strik ingly, however, utrophin immunoreactivity appeared in the granule cell laye r of the DG and became very strong in hypertrophic granule cells 1-2 months post-kainate treatment. These results suggest that utrophin provides struc tural support of neuronal membranes, whereas dystrophin is a component of G ABAergic synapses.