Return of function after CNS axon regeneration: Lessons from injury-responsive intrinsically photosensitive and alpha retinal ganglion cells

This review addresses issues relating to the survival and axon regeneration of both intrinsically photosensitive retinal ganglion cells (ipRGC) and αRGC, and possible ensuing patterns of functional recovery after optic nerve crush, all of which are broadly relevant to recovery from injury in the central nervous system (CNS) as whole. Although much needs to be clarified about the connectivity, function and patterns of myelination of regenerated CNS axons, the results of recent research on activity-induced αRGC axon regeneration associated with functional restitution have highlighted key focal obstacles to recovery including neurotrophic support, axon misguidance, target recognition failure and dysmyelination. Pan RGC survival/axon regeneration requires receptor binding and downstream signalling by a cocktail of growth factors, more generally defined in the CNS by the individual trophic requirements of neuronal subsets within a given disconnected centre. Resolution of the problem of failed axon guidance and target recognition is complicated by a confounding paradox that axon growth inhibitory ligand disinhibition required for axon regeneration may mask axon guidance cues that are essential for accurate re-innervation. The study of the temporal parameters of remyelination of regenerated αRGC axons may become feasible if they establish permanent homologous connections, allowing time for new myelin sheaths to fully form. Unless near complete re-innervation of denervated targets is re-instated in the CNS, debilitating dysfunctional neurological sequelae may ensue from the resulting imbalance in connectivity.