Brain Advance Access published online on March 11, 2008
Brain, doi:10.1093/brain/awn039
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Intrinsic neuronal properties control selective targeting of regenerating motoneurons
1Department of Anatomy and Neurobiology, Sir Charles Tupper Building, Dalhousie University, 5850 College St, Halifax, Nova Scotia, Canada B3H 1X5 and 2Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Program in Cell Biology, Box 290, 1275 York Ave, New York, NY 10021, USA
Correspondence to:
Victor F. Rafuse, PhD, Department of Anatomy and Neurobiology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5 E-mail: vrafuse{at}dal.ca
Despite advances in microsurgical techniques, recovery of motor function after peripheral nerve injury is often poor because many regenerating axons reinnervate inappropriate targets. Consequently, surgical repair must include treatment strategies that improve motor axon targeting. Development of such treatments will require a better understanding of the molecular mechanisms governing selective motor axon targeting. This study used a well-established model of nerve transection and repair to examine (1) whether intrinsic differences exist between different pools of motoneurons after peripheral nerve injury, (2) if such differences regulate selective axon targeting, (3) if regenerating motor axons must express polysialic acid (PSA) in order to preferentially reinnervate muscle and (4) whether brief electrical stimulation improves regeneration accuracy because it increases PSA expression on regenerating axons. We found that different motor pools differentially express PSA after injury and that the capacity to re-express PSA appears to be an intrinsic neuronal property established during development. Second, motoneuron pools not up-regulating PSA did not preferentially reinnervate muscle after injury. Third, brief electrical stimulation of the proximal nerve stump immediately after injury only improved selective motor axon targeting if the motoneurons were capable of up-regulating PSA. Finally, the benefits of stimulation were completely abolished if PSA was removed from the regenerating axons. These results indicate that (1) intrinsic neuronal differences between motor pools must be considered in the development of treatments designed to improve axon targeting and (2) therapeutics aimed at increasing PSA levels on regenerating motor axons may lead to superior functional outcomes.
Key Words: axon guidance; sprouting; NCAM; polysialic acid; electrical stimulation
Abbreviations: PSA, polysialic acid; PMR, preferential motor reinnervation; HSD, Honestly significant difference; ENDO-N, Endoneuraminidase-N
Received October 18, 2007. Revised February 15, 2008. Accepted February 20, 2008.