Almost two weeks ago I commented on neurogenesis in the adult ischemic brain, focusing on the state of regenerative therapy using multipotent neuronal progenitor cells. In this post, however, I’ll address the “plasticity window,” including how neurons cease to make new connections and regenerate in adults, and how physicians might be able to restore this plasticity in order to improve the recoveries of patients with loss of CNS function. (This post is a learning exercise for me as well, as I familiarize myself more with neurogenesis as an area of research, and revolves around one review I read this week: Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?.)
Beginning with the “cost of complexity,” Harel and Strittmatter address what I’d like to use as a starting point: the loss of regenerative capacity in higher mammals. As they note, in feral animals the selective pressure to regenerate after CNS injury is likely extremely small, since such injuries are likely be fatal in the first place. As such, regeneration is a “vestigial” behavior, leftover from our amphibian ancestors, and is only becoming of interest again now that members of our species can survive long enough after CNS injury to look forward to recovery. But even in the adult mammalian CNS, transected nerve fibres appear to at least attempt to regenerate, with proximal stumps of spinal neurons exhibiting a “variable, haphazard regenerative phase.”
Failure of mature neurons to recapitulate damaged circuits is attributed to both intrinsic and extrinsic factors. Harel and Strittmater note that these observations are correlated to neurotrophic factors, neurotransmitters, etc., and early studies on nourishing neurons with has produced some positive results in culture and in animal models of CNS injury. These observations cite possible mechanisms as axonal regeneration, increased neuronal survival, improved remyelination and stimulation of endogenous stem cells. But really very little is known about the molecular basis of these mechanisms, or how to promote them in therapeutic approaches. The authors cite data on a variety of guidance cues in Table 1, but such approaches may be highly specific for individual neurons or very localized regions. Conversely, in my previous post on neurogenesis, I mentioned growth factors, including bFGF, BDNF, EGF, VEGF, and others.
What will be the answer? I don’t know.
- Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Harel NY and Strittmatter SM. Nat Rev Neurosci. 2006 Aug; 7(8):603-16.
- Cajal’s Degeneration and Regeneration of the Nervous System. Ramón y Cajal, S. , DeFelipe, J. & Jones, E. G. (Oxford Univ. Press, New York, 1991). Reviewed by Edwin Clarke