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Stimulation-induced ectopicity and propagation windows in model damaged axons
Neural tissue injuries render voltage-gated Na(+) channels (Nav) leaky, thereby altering excitability, disrupting propagation and causing neuropathic pain related ectopic activity. In both recombinant systems and native excitable membranes, membrane damage causes the kinetically-coupled activation a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224747/ https://www.ncbi.nlm.nih.gov/pubmed/25110188 http://dx.doi.org/10.1007/s10827-014-0521-9 |
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author | Lachance, Mathieu Longtin, André Morris, Catherine E. Yu, Na Joós, Béla |
author_facet | Lachance, Mathieu Longtin, André Morris, Catherine E. Yu, Na Joós, Béla |
author_sort | Lachance, Mathieu |
collection | PubMed |
description | Neural tissue injuries render voltage-gated Na(+) channels (Nav) leaky, thereby altering excitability, disrupting propagation and causing neuropathic pain related ectopic activity. In both recombinant systems and native excitable membranes, membrane damage causes the kinetically-coupled activation and inactivation processes of Nav channels to undergo hyperpolarizing shifts. This damage-intensity dependent change, called coupled left-shift (CLS), yields a persistent or “subthreshold” Nav window conductance. Nodes of Ranvier simulations involving various degrees of mild CLS showed that, as the system’s channel/pump fluxes attempt to re-establish ion homeostasis, the CLS elicits hyperexcitability, subthreshold oscillations and neuropathic type action potential (AP) bursts. CLS-induced intermittent propagation failure was studied in simulations of stimulated axons, but pump contributions were ignored, leaving open an important question: does mild-injury (small CLS values, pumps functioning well) render propagation-competent but still quiescent axons vulnerable to further impairments as the system attempts to cope with its normal excitatory inputs? We probe this incipient diffuse axonal injury scenario using a 10-node myelinated axon model. Fully restabilized nodes with mild damage can, we show, become ectopic signal generators (“ectopic nodes”) because incoming APs stress Na(+)/K(+) gradients, thereby altering spike thresholds. Comparable changes could contribute to acquired sodium channelopathies as diverse as epileptic phenomena and to the neuropathic amplification of normally benign sensory inputs. Input spike patterns, we found, propagate with good fidelity through an ectopically firing site only when their frequencies exceed the ectopic frequency. This “propagation window” is a robust phenomenon, occurring despite Gaussian noise, large jitter and the presence of several consecutive ectopic nodes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10827-014-0521-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4224747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-42247472014-11-12 Stimulation-induced ectopicity and propagation windows in model damaged axons Lachance, Mathieu Longtin, André Morris, Catherine E. Yu, Na Joós, Béla J Comput Neurosci Article Neural tissue injuries render voltage-gated Na(+) channels (Nav) leaky, thereby altering excitability, disrupting propagation and causing neuropathic pain related ectopic activity. In both recombinant systems and native excitable membranes, membrane damage causes the kinetically-coupled activation and inactivation processes of Nav channels to undergo hyperpolarizing shifts. This damage-intensity dependent change, called coupled left-shift (CLS), yields a persistent or “subthreshold” Nav window conductance. Nodes of Ranvier simulations involving various degrees of mild CLS showed that, as the system’s channel/pump fluxes attempt to re-establish ion homeostasis, the CLS elicits hyperexcitability, subthreshold oscillations and neuropathic type action potential (AP) bursts. CLS-induced intermittent propagation failure was studied in simulations of stimulated axons, but pump contributions were ignored, leaving open an important question: does mild-injury (small CLS values, pumps functioning well) render propagation-competent but still quiescent axons vulnerable to further impairments as the system attempts to cope with its normal excitatory inputs? We probe this incipient diffuse axonal injury scenario using a 10-node myelinated axon model. Fully restabilized nodes with mild damage can, we show, become ectopic signal generators (“ectopic nodes”) because incoming APs stress Na(+)/K(+) gradients, thereby altering spike thresholds. Comparable changes could contribute to acquired sodium channelopathies as diverse as epileptic phenomena and to the neuropathic amplification of normally benign sensory inputs. Input spike patterns, we found, propagate with good fidelity through an ectopically firing site only when their frequencies exceed the ectopic frequency. This “propagation window” is a robust phenomenon, occurring despite Gaussian noise, large jitter and the presence of several consecutive ectopic nodes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10827-014-0521-9) contains supplementary material, which is available to authorized users. Springer US 2014-08-12 2014 /pmc/articles/PMC4224747/ /pubmed/25110188 http://dx.doi.org/10.1007/s10827-014-0521-9 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Article Lachance, Mathieu Longtin, André Morris, Catherine E. Yu, Na Joós, Béla Stimulation-induced ectopicity and propagation windows in model damaged axons |
title | Stimulation-induced ectopicity and propagation windows in model damaged axons |
title_full | Stimulation-induced ectopicity and propagation windows in model damaged axons |
title_fullStr | Stimulation-induced ectopicity and propagation windows in model damaged axons |
title_full_unstemmed | Stimulation-induced ectopicity and propagation windows in model damaged axons |
title_short | Stimulation-induced ectopicity and propagation windows in model damaged axons |
title_sort | stimulation-induced ectopicity and propagation windows in model damaged axons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224747/ https://www.ncbi.nlm.nih.gov/pubmed/25110188 http://dx.doi.org/10.1007/s10827-014-0521-9 |
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