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  • Publication : 01 08 2019
  • Catégorie :La recherche médicale et génétique

Hyperexcitability precedes motoneuron loss in the Smn2B/-mouse model of spinal muscular atrophy.    

Abstract
Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state are unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of pre-symptomatic Smn2B/- mice older than one week of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/- mice exhibit more typical postnatal development until postnatal day (P)11/12 and have longer survival (~3 weeks of age). We demonstrate that Smn2B/-motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9-10 and preceded the loss of motor units. We determined that motor unit loss in this mouse model occurred two weeks after birth using MUNE studies. Smn2B/-motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process.

Source : ici