Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.

In injured neurons, "leaky" voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich me...

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Autores principales:	Na Yu, Catherine E Morris, Béla Joós, André Longtin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9ebd75f30c684234b25d9b14f3256cd8
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spelling	oai:doaj.org-article:9ebd75f30c684234b25d9b14f3256cd82021-11-18T05:51:00ZSpontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.1553-734X1553-735810.1371/journal.pcbi.1002664https://doaj.org/article/9ebd75f30c684234b25d9b14f3256cd82012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23028273/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358In injured neurons, "leaky" voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na(+)-loading and "Nav-CLS", i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted I(Na-window). A recent computation study revealed that CLS-based I(Na-window) left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic "smeared" injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For "mild CLS injury", a prominent feature is slow pump/leak-mediated E(Ion) oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist "device" could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms.Na YuCatherine E MorrisBéla JoósAndré LongtinPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 9, p e1002664 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Na Yu Catherine E Morris Béla Joós André Longtin Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.
description	In injured neurons, "leaky" voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na(+)-loading and "Nav-CLS", i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted I(Na-window). A recent computation study revealed that CLS-based I(Na-window) left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic "smeared" injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For "mild CLS injury", a prominent feature is slow pump/leak-mediated E(Ion) oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist "device" could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms.
format	article
author	Na Yu Catherine E Morris Béla Joós André Longtin
author_facet	Na Yu Catherine E Morris Béla Joós André Longtin
author_sort	Na Yu
title	Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.
title_short	Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.
title_full	Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.
title_fullStr	Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.
title_full_unstemmed	Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.
title_sort	spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and na/k pumps.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/9ebd75f30c684234b25d9b14f3256cd8
work_keys_str_mv	AT nayu spontaneousexcitationpatternscomputedforaxonswithinjurylikeimpairmentsofsodiumchannelsandnakpumps AT catherineemorris spontaneousexcitationpatternscomputedforaxonswithinjurylikeimpairmentsofsodiumchannelsandnakpumps AT belajoos spontaneousexcitationpatternscomputedforaxonswithinjurylikeimpairmentsofsodiumchannelsandnakpumps AT andrelongtin spontaneousexcitationpatternscomputedforaxonswithinjurylikeimpairmentsofsodiumchannelsandnakpumps
_version_	1718424803408347136

Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.

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