Résumé :
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Mdx mice provide a model of the human X-linked muscular dystrophy (DMD) caused by mutations in the DMD gene inducing absence of 427-KDa cytoskeletal protein dystrophin. Not only expressed in muscle fibers, dystrophin is also present in the postsynaptic densities (PSDs) of pyramidal cells in cerebral cortex, hippocampus and cerebellum, which may explain the association of DMD with various degrees of cognitive alterations. In the hippocampus, dystrophin is found in perisomatic area and proximal dendrites of CA1-4 pyramidal neurons. In mdx mice, the loss of dystrophin is associated with reduced number and size of GABAA-receptor clusters and abnormal facilitation of CA1 hippocampal long-term potentiation (LTP), suggesting that the memory deficits observed in this model could rely on altered synaptic inhibition and/or imbalanced excitation/inhibition (E/I). The neuronal bases of these alterations, however, have not yet been investigated in detail. Here, we used MRI, light and electron microscopy approaches to investigate possible changes in hippocampal volume, neuron number, and synapse ultrastructure in mdx mice. First we show that dystrophin loss does not affect whole-brain or hippocampal volumes, or the CA1 pyramidal cell density and total synapse number in both the proximal and distal dendritic layers of the CA1 hippocampal subfield. However, we found that the number of axodendritic-inhibitory synapses is enhanced in the proximal dendritic layer of CA1 in mdx mice, a region that normally shows selective expression of dystrophin in association with GABAA receptors. Furthermore, the length of the PSDs is abnormally increased in axospinous perforated-excitatory synapses of mdx mice. Our results suggest that compensatory mechanisms occur during the formation of new inhibitory synapses to counteract a reduced capacity for GABAA-receptor clustering, and we hypothesize that the GABAergic alterations due to dystrophin loss from inhibitory synapses also affect the functional plasticity of glutamatergic synapses.
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