Résumé :
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Schwartz-Jampel syndrome (SJS) is a recessive disorder characterized by spontaneous activity in the rest EMG that may result from peripheral nerve hyperexcitability (PNH). SJS results from a lack of perlecan, the major proteoglycan of basement membranes (BMs). Since BM is important for myelination and formation of nodes of Ranvier, we determined whether peripheral nervous system (PNS) changes occurred when perlecan is lacking by studying a mouse model of SJS that develops PNH with ageing. Perlecan immunostaining decreased by 70% in the internodal and nodal BMs of mutant mice compared to littermate wild-type mice, used as controls. Ultrastructural analyses of sciatic nerves from 8 month-old mutants, which displayed spontaneous activity in the rest EMG of hindlimb muscles, did not show major changes except for some polyaxonal myelination and a shift toward smaller nerve fibers. Moreover, the survey of compact myelin by FM1-43 staining did not detect focal demyelination on dilacerated sciatic nerve fibers of 8 month-old mutants but showed abnormal staining of some myelin borders flanking nodes of Ranvier, suggesting nodal disorganization. Accordingly, an increased width of Na+ (node) and Caspr (paranode) staining was observed for 15% of nodes of Ranvier in 8 month-old mutants when compared to age-matched controls. The overall organization of nodes was found to be conserved by immunostaining except for gliomedin (microvilli marker), which was mislocalized in 8 but not in 2 month-old mutants, a younger age at which no spontaneous activity was recorded in hindlimb muscles. Reduced internodal length, increased number of juxtaincisures and Schmidt-Lanterman incisures, and increased intensity of juxtaparanodal Kv1.1 and Kv1.2 staining were observed in both 2 and 8 month-old mutants compared to age-matched controls. Evaluation of sciatic nerve excitability in vitro at 35_C detected a higher sensitivity of axonal membranes to extracellular K+ concentration when evaluation of neuromuscular excitability in vivo, using the threshold tracking technique, showed mild changes involving K+ channels in 8 month-old mutants compared to controls. Altogether, our results strongly suggest that perlecan is required for the development and the maintenance of axon-glia and glia-glia interactions. The relationships of the changes observed with PNH are under investigation.Supported by AFM, NeRF, INSERM, CNRS, UPMC, and MESR.
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