This chapter discusses current knowledge of how precisely ordered afferent synaptogenesis occurs during development. It also explains the potential for reforming functional circuits by correct rewiring during regeneration. Most of the knowledge of the mechanisms involved in establishing circuits between distant central nervous system (CNS) neuronal populations comes from studies of the axonal projection from the eye to central brain targets. The output neurons of the eye are the retinal ganglion cells (RGCs), whose axons exit the eye as the optic nerve, cross the midline at the optic chiasm, and innervate central brain structures. RGCs in fish and frogs survive optic nerve lesion and sprout new axonal extensions that correctly navigate to the tectum, reform the retinotectal map, and demonstrate visual responsivity. Regeneration recapitulates a critical period of heightened plasticity during which activity-dependent mechanisms mediate map refinement through pruning of ectopic axonal branches.

This chapter outlines some of the various components which may contribute to the observed lack of regeneration which occurs after injury to the adult mammalian central nervous system (CNS). To date, three major inhibitors of axonal regeneration associated with myelin have been identified: myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp). The myelin-associated inhibitors all appear to be present in undamaged myelin and may have roles other than the block of regeneration or inadvertent sprouting. Following the binding of each of the myelin-associated inhibitors to the NgR-p75NTR-LINGO receptor complex, there is an induction of a signaling pathway which eventually leads to the blockage of neurite extension from damaged or naïve adult neurons. If the binding or signaling of a single receptor complex can be compromised, it may be possible to permit sufficient regeneration in the adult mammalian CNS after injury, particularly prior to formation of the glial scar.