Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?

Abstract

Adult mammalian CNS regeneration is limited by a combination of intrinsic and extrinsic inhibitory barriers. This differs from the extraordinary ability to form short- and long-distance connections and complex circuits during nervous system development. Various signalling molecules guide developing neuronal branches. Many of these molecules persist in adults, but in different quantitative and qualitative distributions. The immature nervous system is refined by experience-dependent plasticity, resulting in the pruning of unnecessary connections and strengthening of useful ones. Mechanisms responsible for consolidating these refinements largely prevent further plastic changes, and secondarily inhibit regenerative responses in the context of injury. Local network circuits termed central pattern generators (CPGs) regulate semi-automatic behaviours such as ambulation. CPG plasticity and adaptation depend on sensory feedback and voluntary input. Intrinsic barriers to CNS regeneration include an unfavourable intracellular second messenger milieu as well as the inability to use regeneration-associated genes. Extrinsic barriers to CNS regeneration include inhibitory molecules produced by oligodendrocytes, astrocytes and inflammatory cells. The altered distribution of growth and guidance factors in the adult relative to the developing nervous systems represents another extrinsic barrier to effective regeneration. Advances using stem cells, neurotrophins and antagonists of extracellular inhibitors have resulted in a limited degree of CNS regeneration so far. Better approaches are required to recapitulate the precision of developmental growth, guidance and plasticity mechanisms. One strategy to mimic the developmental milieu requires better understanding of the changes in distribution of key guidance molecules during and after development. Rehabilitation approaches that maximize sensory feedback to CPGs will optimize the adaptation to loss of descending voluntary input.