Liz Bradbury’s Lab: Conduction at Chronic Stages


  • Development/Plasticity/Repair

Conduction Failure following Spinal Cord Injury: Functional and Anatomical Changes from Acute to Chronic Stages

  1. Nicholas D. James,
  2. Katalin Bartus,
  3. John Grist,
  4. David L. H. Bennett,
  5. Stephen B. McMahon, and
  6. Elizabeth J. Bradbury

+Author Affiliations

  1. The Wolfson Centre for Age-Related Diseases, King’s College London, London SE1 1UL, United Kingdom
  1. Author contributions: D.L.H.B., S.B.M., and E.J.B. designed research; N.D.J., K.B., and J.G. performed research; N.D.J. and K.B. analyzed data; N.D.J. and E.J.B. wrote the paper.

Abstract

In the majority of spinal cord injuries (SCIs), some axonal projections remain intact. We examined the functional status of these surviving axons since they represent a prime therapeutic target. Using a novel electrophysiological preparation, adapted from techniques used to study primary demyelination, we quantified conduction failure across a SCI and studied conduction changes over time in adult rats with a moderate severity spinal contusion (150 kdyn; Infinite Horizon impactor). By recording antidromically activated single units from teased dorsal root filaments, we demonstrate complete conduction block in ascending dorsal column axons acutely (1–7 d) after injury, followed by a period of restored conduction over the subacute phase (2–4 weeks), with no further improvements in conduction at chronic stages (3–6 months). By cooling the lesion site, additional conducting fibers could be recruited, thus revealing a population of axons that are viable but unable to conduct under normal physiological conditions. Importantly, this phenomenon is still apparent at the most chronic (6 month) time point. The time course of conduction changes corresponded with changes in behavioral function, and ultrastructural analysis of dorsal column axons revealed extensive demyelination during the period of conduction block, followed by progressive remyelination. A proportion of dorsal column axons remained chronically demyelinated, suggesting that these are the axons recruited with the cooling paradigm. Thus, using a clinically relevant SCI model, we have identified a population of axons present at chronic injury stages that are intact but fail to conduct and are therefore a prime target for therapeutic strategies to restore function.
This experiment showed individual nerve fibers, in a living animal, that long nerve fibers survive a spinal cord injury contusion in a chronic model (six months for rats) conduction was partly restored by modifying the physiology of the injury area. This is the first time that conduction changes in individual fibers have been assessed in vivo following spinal contusion in the adult rat. The nerve axons were able to conduct signals after being cooled – this lowers the threshold for activating nerve potentials. Intact surviving axons exist and are therefore targets for some type of therapy.
By recording antidromically activated [conduction opposite of the normal direction] single units from teased dorsal root filaments, we demonstrate complete conduction block in ascending dorsal column axons acutely (1–7 d) after injury,followed by a period of restored conduction over the subacute phase (2– 4 weeks), with no further improvements in conduction at chronic stages (3– 6 months). By cooling the lesion site, additional conducting fibers could be recruited, thus revealing a population of axons that are viable but unable to conduct under normal physiological conditions. Importantly, this phenomenon is still apparent at the most chronic (6 month) time point. Importantly, by cooling the lesion site, we show enhanced conduction across the contusion injury, even in a chronic SCI. Thus, we have documented the time course over which viable but initially nonconducting axons regain a useful functionality and reveal a population of surviving axons that remain chronically unable to conduct under normal physiological conditions and that represent an important population to target therapeutically. In the present study, we found that despite extensive remyelination at 12 weeks after injury there remained a small but significant proportion of demyelinated axons. Importantly, we also demonstrate that, even in chronic stages of SCI, conduction can be restored to some axons upon cooling; these are most likely to be the chronically demyelinated axons observed by EM [electron microscope]. This further demonstrates the potential of viable but nonconducting axons as important therapeutic targets. Whether such therapies should involve remyelination, or other methods of reducing conduction block, remains for further study.
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