Enhancing axon regeneration in peripheral nerves also increases functionally inappropriate reinnervation of targets

The specificity of reinnervation of peripheral targets by regenerating motor axons was studied in mice by using retrograde fluorescent tracers applied to the cut ends of the tibial and common fibular nerves after transection and surgical repair of the sciatic nerve. When the nerve ends were aligned and secured with fibrin glue, more motoneurons labeled after application of tracer to the common fibular nerve were found in regions of the spinal cord that normally contain only tibial motoneurons. The magnitude of such inappropriate reinnervation did not change at different times after repair. Intentional misalignment of the cut nerve stumps at the time of repair resulted in more extensive inappropriate reinnervation of the different peripheral targets. If the proximal stump of the cut nerve was electrically stimulated at the time of repair, if the distal stump was treated with chondroitinase ABC, or if both protocols were applied, the number of motoneurons labeled was increased. This increase was accompanied by more extensive reinnervation of inappropriate targets than found after untreated nerve repair. Although alterations in the caudorostral distributions of labeled motoneurons observed were not as great as observed after purposeful misalignment of the cut nerve ends, the topographic relationship between the spinal locations of motoneuron somata and the peripheral targets of their axons is disrupted. Enhancement of motor axon regeneration by induction of growth-promoting signaling pathways, reduction in growth inhibition in the environment of regenerating axons, or both, is accompanied by an increase in the amount of functionally inappropriate reinnervation of peripheral targets.