Putative roles of soluble trophic factors in facial nerve regeneration, target reinnervation, and recovery of vibrissal whisking

Abstract

It is well-known that, after nerve transection and surgical repair, misdirected regrowth of regenerating motor axons may occur in three ways. The first way is that the axons enter into endoneurial tubes that they did not previously occupy, regenerate through incorrect fascicles and reinnervate muscles that they did not formerly supply. Consequently the activation of these muscles results in inappropriate movements. The second way is that, in contrast with the precise target-directed pathfinding by elongating motor nerves during embryonic development, several axons rather than a single axon grow out from each transected nerve fiber. The third way of misdirection occurs by the intramuscular terminal branching (sprouting) of each regenerating axon to culminate in some polyinnervation of neuromuscular junctions, i.e. reinnervation of junctions by more than a single axon. Presently, "fascicular" or "topographic specificity" cannot be achieved and hence target-directed nerve regeneration is, as yet, unattainable. Nonetheless, motor and sensory reinnervation of appropriate endoneurial tubes does occur and can be promoted by brief nerve electrical stimulation. This review considers the expression of neurotrophic factors in the neuromuscular system and how this expression can promote functional recovery, with emphasis on the whisking of vibrissae on the rat face in relationship to the expression of the factors. Evidence is reviewed for a role of neurotrophic factors as short-range diffusible sprouting stimuli in promoting complete functional recovery of vibrissal whisking in blind Sprague Dawley (SD)/RCS rats but not in SD rats with normal vision, after facial nerve transection and surgical repair. Briefly, a complicated time course of growth factor expression in the nerves and denervated muscles include (1) an early increase in FGF2 and IGF2, (2) reduced NGF between 2 and 14days after nerve transection and surgical repair, (3) a late rise in BDNF and (4) reduced IGF1 protein in the denervated muscles at 28days. These findings suggest that recovery of motor function after peripheral nerve injury is due, at least in part, to a complex regulation of nerve injury-associated neurotrophic factors and cytokines at the neuromuscular junctions of denervated muscles. In particular, the increase of FGF2 and concomittant decrease of NGF during the first week after facial nerve-nerve anastomosis in SD/RCS blind rats may prevent intramuscular axon sprouting and, in turn, reduce poly-innervation of the neuromuscular junction.

Keywords: Axotomy; BDNF; FGF2; Functional recovery; IGF; Motoneuron; Motor endplates; NGF; Polyinnervation; Vibrissae whisking.