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Primary paranode demyelination modulates slowly developing axonal depolarization in a model of axonal injury

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Abstract

Neurological sequelae of mild traumatic brain injury are associated with the damage to white matter myelinated axons. In vitro models of axonal injury suggest that the progression to pathological ruin is initiated by the mechanical damage to tetrodotoxin-sensitive voltage-gated sodium channels that breaches the ion balance through alteration in kinetic properties of these channels. In myelinated axons, sodium channels are concentrated at nodes of Ranvier, making these sites vulnerable to mechanical injury. Nodal damage can also be inflicted by injury-induced partial demyelination of paranode/juxtaparanode compartments that flank the nodes and contain high density of voltage-gated potassium channels. Demyelination-induced potassium deregulation can further aggravate axonal damage; however, the role of paranode/juxtaparanode demyelination in immediate impairment of axonal function, and its contribution to the development of axonal depolarization remain elusive. A biophysically realistic computational model of myelinated axon that incorporates ion exchange mechanisms and nodal/paranodal/juxtaparanodal organization was developed and used to study the impact of injury-induced demyelination on axonal signal transmission. Injured axons showed alterations in signal propagation that were consistent with the experimental findings and with the notion of reduced axonal excitability immediately post trauma. Injury-induced demyelination strongly modulated the rate of axonal depolarization, suggesting that trauma-induced damage to paranode myelin can affect axonal transition to degradation. Results of these studies clarify the contribution of paranode demyelination to immediate post trauma alterations in axonal function and suggest that partial paranode demyelination should be considered as another “injury parameter” that is likely to determine the stability of axonal function.

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Acknowledgments

This work was sponsored by the US Army Medical Research and Materiel Command under contract W81XWH-11-D-0011. This document is cleared for all audiences for OPSEC purposes. Cleared 09/18/2013. The opinions or assertions contained herein are private views of the authors, and are not to be construed as official or as reflecting views of the Department of the Army or the Department of Defense. PAO REVIEWED. The authors declare no competing financial interests.

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  1. L-3 Applied Technologies/Simulation, Engineering, & Testing, 10770 Wateridge Circle, Suite 200, San Diego, CA, 92121, USA

    Vladislav Volman & Laurel J. Ng

  2. Center for Theoretical Biological Physics, University California at San Diego, La Jolla, CA, 92093, USA

    Vladislav Volman

  3. Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA

    Vladislav Volman

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Volman, V., Ng, L.J. Primary paranode demyelination modulates slowly developing axonal depolarization in a model of axonal injury. J Comput Neurosci 37, 439–457 (2014). https://doi.org/10.1007/s10827-014-0515-7

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