Influence of brief electrical stimulation on peripheral nerve regeneration in heterozygous trkB deficient mice

Abstract

Functional recovery after peripheral axonal injury is often insufficient and several treatments to improve neuronal regeneration have been investigated. Brief electrical stimulation, for instance, has previously been shown to accelerate axonal sprouting and distal nerve stump reinnervation, up-regulate regeneration-associated genes and accelerate functional recovery after peripheral nerve injury. These effects are believed to be mediated by BDNF and its high-affinity receptor trkB, which are up-regulated after axonal injury. Here, the effects of short-term low-frequency brief electrical stimulation (1 h, 20 Hz) after femoral nerve injury and immediate nerve repair on (1) functional recovery, (2) neuronal survival and (3) precision of reinnervation were investigated in heterozygous trkB deficient mice (trkB+/-) compared to their wild-type littermates (trkB+/+) in the femoral nerve paradigm. Recovery of the quadriceps muscle function was assessed by single-frame motion analysis over a post-operative period of 3 months, while axonal reinnervation of the distal nerve stump was evaluated morphologically using retrograde labelling after 12 weeks of recovery. The results showed that functional recovery was worse in trkB+/- mice compared to their wild-type littermates at 2-8 weeks after injury but the final outcome at 12 weeks was similar in the two genotypes. Morphological analysis revealed, in accordance with the functional data, a similar degree of motoneuronal regeneration and no preferential motor reinnervation in the two genotypes. The findings of worse functional recovery during the first 2 month after injury in heterozygous trkB versus wild-type mice is apparently related to reduced trkB expression and provides further evidence that enhances trkB signalling underlies the effect of brief electrical stimulation on nerve regeneration. The amount of trkB expressed in the heterozygous mouse is, however, obviously sufficient to compensate, at late time points after injury, for initial deficits in regeneration.