Glial inhibition of CNS axon regeneration

Damage to the adult central nervous system (CNS) often results in lasting disabilities because mature nerve fibers (axons) cannot regrow after injury. The glial environment, including inhibitory molecules in myelin and proteoglycans in astroglial scars, hinders axon regeneration. Researchers are studying the molecular basis of these inhibitory influences to understand why long-distance axon repair and structural plasticity are limited. Understanding glial inhibition is crucial for developing therapies that promote functional recovery after neural injury. The failure of axons to regenerate in the adult CNS may be due to a decline in the intrinsic growth ability of neurons and the presence of inhibitory or repulsive guidance cues that persist into adulthood. The glial environment differs from the PNS, with myelin structure and glial scars acting as barriers.

• 1
  CNS myelin and glial scars inhibit axon outgrowth, but their relative importance in vivo is uncertain. Myelin inhibitors are constitutively expressed, while CSPGs are strongly upregulated following injury, with different time courses of expression ranging from 24 hours to 6 months post-lesion.
• 2
  Receptor mechanisms for myelin inhibition have been elucidated, including the Nogo-66 receptor (NgR) and transmembrane co-receptors such as p75, TROY, and LINGO1. However, recent studies using NgR-mutant mice have challenged the oversimplified scenario that the NgR complex is the major receptor for myelin-associated signals.
• 3
  Intracellular signaling pathways, such as RhoA/ROCK, PKC, and EGFR, are common to multiple sources of inhibition and could offer a greater prospect for promoting axon regeneration. These pathways mediate myelin inhibition and are also triggered by CSPGs.