Prolonged high frequency electrical stimulation is lethal to motor axons of mice heterozygously deficient for the myelin protein P0 gene

The relationship between dysmyelination and the progression of neuropathy in Charcot-Marie-Tooth (CMT) hereditary polyneuropathy is unclear. Mice heterozygously deficient for the myelin protein P0 gene (P0+/−) are indistinguishable from wild-type (WT) at birth and then develop a slowly progressing demyelinating neuropathy reminiscent of CMT Type 1b. Accumulating evidence suggests that impulse conduction can become lethal to acutely demyelinated central and peripheral axons. Here we investigated the vulnerability of motor axons to long-lasting, high-frequency repetitive stimulation (RS) in P0+/− mice as compared to WT littermates at 7, 12, and 20 months of age. RS was carried out in interrupted trains of 200 Hz trains for 3 h. Tibial nerves were stimulated at the ankle while the evoked compound muscle action potentials (CMAPs) and the ascending compound nerve action potentials (CNAPs) were recorded from plantar muscles and the sciatic nerve, respectively. In 7-month old mice, there was recovery of CMAP and CNAP following RS. When mice were about one year old, electrophysiological recovery following RS was incomplete and in P0+/− also associated with morphological signs of partial Wallerian degeneration. The effect of RS was larger in P0+/− as compared to age-matched WT. When mice were about 2 years old, the effect was stronger and became similar between WT and P0+/−. RS was followed by a transient hyperpolarization, which decreased with age and was smaller in P0+/− than in WT. Our data suggest that both aging and the dysmyelinating disease process may contribute to the susceptibility to activity-induced axonal degeneration. It is possible that in aging mice and in P0+/− there is inadequate energy-dependent Na+/K+ pumping, as indicated by the reduced post-stimulation hyperpolarization, which may lead to a lethal Na+ overload in some axons.

► Heterozygot P0 deficient mice have a progressive dysmyelinating neuropathy. ► We investigated the effect of strenuous repetitive stimulation (RS) in P0+/− mice. ► Axonal loss following RS increased with aging and dysmyelination. ► Extent of hyperpolarization following RS decreased with aging and dysmyelination. ► Susceptibility to activity could be due to impaired energy-dependent Na +-pumping.