The poor regenerative capacity of axons in the central nervous system (CNS) is still a serious obstacle to CNS repair. However, two new studies published in Neuron, by Qiu et al. and Neumann et al., indicate that a solution to this problem might come from studying how dorsal root ganglion (DRG) neurons respond to peripheral damage.

The primary sensory neurons of the DRG have axonal branches in both the peripheral nervous system and the spinal cord. But whereas the peripheral branch can regenerate after injury, the central branch cannot. Intriguingly, however, if the peripheral branch is lesioned first, the regenerative capacity of the central branch is increased considerably. The authors of these studies reasoned that if they could identify the signalling pathways that are activated by this so-called 'conditioning lesion', they might be able to mimic its effects without causing further damage.

It was previously shown that raising the levels of cyclic AMP signalling in CNS neurons allows them to grow on myelin, which normally inhibits their growth. Qiu et al. showed that cAMP levels were raised in DRG neurons in response to a peripheral lesion, so they asked whether cAMP signalling was required for the conditioning effect. They found that, in the presence of a cAMP inhibitor, a peripheral lesion could no longer stimulate central axonal growth, providing strong evidence that the conditioning response is mediated by cAMP signalling.

Could cAMP signalling mimic the effects of a peripheral lesion on central axonal regeneration? Both teams increased the level of cAMP signalling in primary sensory neurons by injecting a cAMP analogue into the DRG, where the cell bodies of these neurons are located. They found that this treatment did indeed cause central axons to regenerate in the absence of a peripheral lesion. In addition, Neumann et al. showed that this treatment has a dual effect — it not only helps the axon to overcome the inhibitory effects of myelin, but also increases its intrinsic capacity for growth.

So, the conditioning effect of a peripheral lesion can be reproduced by stimulating cAMP signalling in the DRG. The fact that this intervention can be carried out at the level of the cell body means that it is not necessary to inflict further trauma on the site of injury, raising the possibility that it could lead to a viable clinical treatment for spinal cord damage. At a more fundamental level, it will also be interesting to elucidate the molecular basis of the asymmetrical response of DRG neuronal processes to injury.