Résumé :
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Spinal Muscular Atrophy (SMA), a lethal neurodegenerative disease which occurs in childhood, is due to the misexpression of the survival-motor-neuron (SMN) proteinin motor-neurons. We have evaluated the effect of a running-based training (Grondard et al., 2005) on type 2 SMA-like mice Smn _7/_7, Smn2+/+ (Hsieh-Li et al.,2000). The results have shown a gain in motor function and life span (+60%), an acceleration of muscles and neuromuscular junctions maturation, a reduction ofmotor-neurons death in the lumbar anterior horn of the spinal cord and an increase in exon7-containing SMN transcripts. We have also shown that the specific inhibitionof NMDA-receptor abolished the exercise-induced effects (Biondi et al., 2008).In the present work, we demonstrate the benefits of an adequate NMDA-receptor activation(5 pmol/g/d in 0.9% NaCl) in the type 2 SMA-like mice. This treatment significantly accelerated motor-unit postnatal maturation, counteracted motor-neurons deathin the spinal cord and induced a marked increase in SMN expression resulting from the insertion of the exon 7 in the SMN transcripts generated from SMN2 gene.Furthermore, the type 2 SMA-like mice lifespan is considerably extended. The analysis of the intracellular signaling cascade that lay downstream the activated NMDAreceptorrevealed an unexpected reactivation of the CaMKII/AKT/CREB pathway that induced an enhanced SMN expression. Therefore, pharmacological activation ofspinal NMDA-receptors could constitute a useful strategy for both increasing SMN expression and limiting motor-neurons death in SMA spinal cord.
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