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


: Dr Jean-Marc Fritschy, as above.


Dystrophin and its autosomal homologue utrophin are coexpressed in muscle cells, and utrophin is functionally able to replace dystrophin in models of Duchenne muscular dystrophy. In brain, the two proteins are expressed differentially, suggesting distinct functional roles. Dystrophin is associated with postsynaptic GABAA receptors in hippocampus, cortex and cerebellum, whereas utrophin is present extrasynaptically, notably in large brainstem neurons. Here, the regulation of dystrophin and utrophin was investigated in a model of temporal lobe epilepsy. Adult mice were injected unilaterally with kainic acid into the dorsal hippocampus to induce loss of pyramidal cells and hypertrophy of dentate gyrus (DG) granule cells, as described (Suzuki, F., Junier, M.P., Guilhem, D., Sorensen, J.C. & Onteniente, B. (1995)Neuroscience, 64, 665–674.). These morphological changes were associated with an increase in postsynaptic GABAA-receptors in the ipsilateral DG, as demonstrated by a parallel increase in punctate immunoreactivity to GABAA-receptor α2 subunit, gephyrin and dystrophin in the molecular layer. Thus, both dystrophin and gephyrin were involved in postsynaptic clustering of GABAA receptors. A transient induction of utrophin was seen at the onset of degeneration in CA1 and CA3 pyramidal cells and in the hilus. Most strikingly, however, utrophin immunoreactivity appeared in the granule cell layer of the DG and became very strong in hypertrophic granule cells 1–2 months post-kainate treatment. These results suggest that utrophin provides structural support of neuronal membranes, whereas dystrophin is a component of GABAergic synapses.

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