Chapter 9 - Axon regeneration

Abstract

Axonal damage and degeneration is a major feature of traumatic brain injury, spinal cord injury, stroke, and numerous neurodegenerative disorders. In adult mammals, including humans, the regenerative capacity of injured central nervous system (CNS) neurons is very limited, leading to permanent functional deficits. Depending on the location and severity, CNS injury or disease typically results in neurological deficits ranging from mild motor impairment to complete paralysis and from mild cognitive deficits to severe dementia and death. A major goal of regenerative medicine is to reestablish neuronal connectivity and function lost as a consequence of injury or disease. In theory, this can be achieved by (1) long-distance regeneration of severed axons, followed by target innervation and synapse formation; (2) short-distance axonal growth and synapse formation on neural elements that form relays to neuronal targets distal to the injury site; and (3) activation of spared neuronal ensembles that maintain connectivity beyond the injury site. In the adult mammalian CNS, there are numerous barriers to spontaneous CNS axon regeneration and target reinnervation, broadly divided into environmental or extrinsic influences and an intrinsic failure of injured neurons to activate and sustain a growth response. Because spontaneous axon regeneration is frequently observed in the injured adult mammalian peripheral nervous system, as well as in the CNS of lower vertebrates, comparative analyses of the underlying cellular and molecular mechanisms have uncovered similarities and important differences that may be exploited therapeutically to promote axonal regeneration in the injured or diseased mammalian CNS. In recent years, substantial progress has been made in our understanding of how axonal growth is regulated in mature neurons. This resulted in the development of experimental therapies that enable long-distance axon regeneration in CNS-injured rodents and nonhuman primates. Challenges ahead include translation of the most promising advances to CNS-injured human subjects.