Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3

James M. Massey, Jeremy Amps, Mariano S. Viapiano, Russell T. Matthews, Michelle R. Wagoner, Christopher M. Whitaker, Warren Alilain, Alicia L. Yonkof, Abdelnaby Khalyfa, Nigel G.F. Cooper, Jerry Silver, Stephen M. Onifer

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

Abstract

Increased chondroitin sulfate proteoglycan (CSPG) expression in the vicinity of a spinal cord injury (SCI) is a primary participant in axonal regeneration failure. However, the presence of similar increases of CSPG expression in denervated synaptic targets well away from the primary lesion and the subsequent impact on regenerating axons attempting to approach deafferented neurons have not been studied. Constitutively expressed CSPGs within the extracellular matrix and perineuronal nets of the adult rat dorsal column nuclei (DCN) were characterized using real-time PCR, Western blot analysis and immunohistochemistry. We show for the first time that by 2 days and through 3 weeks following SCI, the levels of NG2, neurocan and brevican associated with reactive glia throughout the DCN were dramatically increased throughout the DCN despite being well beyond areas of trauma-induced blood brain barrier breakdown. Importantly, regenerating axons from adult sensory neurons microtransplanted 2 weeks following SCI between the injury site and the DCN were able to regenerate rapidly within white matter (as shown previously by Davies et al. [Davies, S.J., Goucher, D.R., Doller, C., Silver, J., 1999. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 5810-5822]) but were unable to enter the denervated DCN. Application of chondroitinase ABC or neurotrophin-3-expressing lentivirus in the DCN partially overcame this inhibition. When the treatments were combined, entrance by regenerating axons into the DCN was significantly augmented. These results demonstrate both an additional challenge and potential treatment strategy for successful functional pathway reconstruction after SCI.

Original languageEnglish
Pages (from-to)426-445
Number of pages20
JournalExperimental Neurology
Volume209
Issue number2
DOIs
StatePublished - Feb 2008

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health NS40411 (S.M.O.), RR15576 (S.M.O.), NS25713 (J.S.), and RR16481 (N.G.F.C.). J.M.M. was supported by a fellowship awarded from the Kentucky National Science Foundation/Experimental Program to Stimulate Competitive Research EPS-9874764 (N.G.F.C.) and by the Summer Research Scholars Program at the School of Medicine in the University of Louisville. The authors extend their appreciation to the Stan Gerson (Case Western Reserve University) and S. O'Gorman (Case Western Reserve University) laboratories and to Justin Roth for their expertise and technical assistance in development of the lentiviral vectors used in our experiments. We also thank Richard Benton, Qiang He, Julie Decker and Polly Fleck for their expert technical assistance and Aaron Puckett and the University of Louisville Research Resources Center veterinarians and staff for their excellent assistance with veterinary care.

Keywords

  • Aggrecan
  • Axonal plasticity
  • Brevican
  • Dorsal column nuclei
  • Gliosis
  • Inflammation
  • Lentivirus
  • NG2
  • Neurocan
  • Perineuronal nets

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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