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Journal of Computational Neuroscience

, Volume 33, Issue 2, pp 301–319 | Cite as

Coupled left-shift of Nav channels: modeling the Na+-loading and dysfunctional excitability of damaged axons

  • Pierre-Alexandre Boucher
  • Béla Joós
  • Catherine E. Morris
Article

Abstract

Injury to neural tissue renders voltage-gated Na+ (Nav) channels leaky. Even mild axonal trauma initiates Na+ -loading, leading to secondary Ca2+-loading and white matter degeneration. The nodal isoform is Nav1.6 and for Nav1.6-expressing HEK-cells, traumatic whole cell stretch causes an immediate tetrodotoxin-sensitive Na+-leak. In stretch-damaged oocyte patches, Nav1.6 current undergoes damage-intensity dependent hyperpolarizing- (left-) shifts, but whether left-shift underlies injured-axon Nav-leak is uncertain. Nav1.6 inactivation (availability) is kinetically limited by (coupled to) Nav activation, yielding coupled left-shift (CLS) of the two processes: CLS should move the steady-state Nav1.6 “window conductance” closer to typical firing thresholds. Here we simulated excitability and ion homeostasis in free-running nodes of Ranvier to assess if hallmark injured-axon behaviors—Na+-loading, ectopic excitation, propagation block—would occur with Nav-CLS. Intact/traumatized axolemma ratios were varied, and for some simulations Na/K pumps were included, with varied in/outside volumes. We simulated saltatory propagation with one mid-axon node variously traumatized. While dissipating the [Na+] gradient and hyperactivating the Na/K pump, Nav-CLS generated neuropathic pain-like ectopic bursts. Depending on CLS magnitude, fraction of Nav channels affected, and pump intensity, tonic or burst firing or nodal inexcitability occurred, with [Na+] and [K+] fluctuating. Severe CLS-induced inexcitability did not preclude Na+-loading; in fact, the steady-state Na+-leaks elicited large pump currents. At a mid-axon node, mild CLS perturbed normal anterograde propagation, and severe CLS blocked saltatory propagation. These results suggest that in damaged excitable cells, Nav-CLS could initiate cellular deterioration with attendant hyper- or hypo-excitability. Healthy-cell versions of Nav-CLS, however, could contribute to physiological rhythmic firing.

Keywords

Hodgkin-Huxley Diffuse axonal injury Myelinated Arrhythmia Neuropathic pain Na/K-ATPase Extracellular space 

Notes

Acknowledgements

We thank André Longtin and Na Yu for helpful discussions during the preparation of this manuscript. Our research was supported by funds from NSERC, HSF and CIHR.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of PhysicsUniversity of OttawaOttawaCanada
  2. 2.NeurosciencesOttawa Hospital Research InstituteOttawaCanada

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