Glial inhibition of CNS axon regeneration

Abstract

Damage to the adult CNS leads to persistent deficits owing to the inability of CNS axons to regenerate after injury. This regeneration failure is attributable to the reduced intrinsic growth ability of mature neurons and extrinsic inhibitory influences from the glial environment, such as inhibitory molecules in CNS myelin and chondroitin sulphate proteoglycans (CSPGs) from the glial scar. Many myelin-associated inhibitors have been identified using in vitro assays, including Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp). Repulsive guidance cues that are important during development, such as ephrin B3 and semaphorin 4D, might also persist in the adult and limit axon growth. CSPGs expressed by reactive astrocytes can inhibit axon regeneration through their protein core or glycosaminoglycan moieties. Although both CNS myelin and CSPGs are likely to contribute to regeneration failure, their relative importance remains uncertain. Although receptor mechanisms for CSPGs are not known, most myelin inhibitors signal through a common receptor complex that consists of the Nogo-66 receptor (NgR) and its co-receptors p75 or TROY and LINGO1. Recent evidence from genetic deletion studies, however, suggests that there are also NgR-independent signalling pathways. Common intracellular mechanisms probably mediate both CNS myelin and CSPG-based inhibition. The best-characterized pathway involves the small GTPase RhoA and its effector Rho-associated kinase (ROCK), which can regulate the actin cytoskeleton. Calcium-related signals, including protein kinase C and epidermal growth factor (EGFR), might also be involved in these inhibitory pathways. Many in vivo studies have targeted these inhibitory ligands, receptors and downstream components to promote regeneration after spinal cord injury. Whereas some pharmacological and dominant-negative approaches have shown promise, most knockout studies have met with limited success. These results demonstrate the complexity and cross-compensation between the different inhibitory influences, and the potential existence of as yet unidentified mechanisms. Recent reports are revealing intriguing parallels between the mechanisms that prevent axon repair after CNS injury, and those that limit experience-dependent plasticity. Even in the absence of long-distance axon regeneration, recovery from CNS injuries might benefit from local sprouting and structural plasticity similar to the way in which sensory experience fine-tunes neural circuits during the critical period. Alleviating glial inhibition might not only promote the regrowth of damaged axons, but might also enhance recovery through local compensatory sprouting. Combinatorial approaches that target multiple inhibitory pathways and promote the intrinsic growth ability of neurons might be necessary to achieve significant long-distance regeneration.