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Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation
BACKGROUND: Neurological manifestations of severe coronavirus infections, including SARS-CoV-2, are wide-ranging and may persist following virus clearance. Detailed understanding of the underlying changes in brain function may facilitate the identification of therapeutic targets. We directly tested...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575822/ https://www.ncbi.nlm.nih.gov/pubmed/37833408 http://dx.doi.org/10.1186/s40635-023-00557-9 |
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author | Rajayer, Salil R. Smith, Stephen M. |
author_facet | Rajayer, Salil R. Smith, Stephen M. |
author_sort | Rajayer, Salil R. |
collection | PubMed |
description | BACKGROUND: Neurological manifestations of severe coronavirus infections, including SARS-CoV-2, are wide-ranging and may persist following virus clearance. Detailed understanding of the underlying changes in brain function may facilitate the identification of therapeutic targets. We directly tested how neocortical function is impacted by the specific panel of cytokines that occur in coronavirus brain infection. Using the whole-cell patch-clamp technique, we determined how the five cytokines (TNFα, IL-1β, IL-6, IL-12p40 and IL-15 for 22–28-h) at concentrations matched to those elicited by MHV-A59 coronavirus brain infection, affected neuronal function in cultured primary mouse neocortical neurons. RESULTS: We evaluated how acute cytokine exposure affected neuronal excitability (propensity to fire action potentials), membrane properties, and action potential characteristics, as well as sensitivity to changes in extracellular calcium and magnesium (divalent) concentration. Neurovirulent cytokines increased spontaneous excitability and response to low divalent concentration by depolarizing the resting membrane potential and hyperpolarizing the action potential threshold. Evoked excitability was also enhanced by neurovirulent cytokines at physiological divalent concentrations. At low divalent concentrations, the change in evoked excitability was attenuated. One hour after cytokine removal, spontaneous excitability and hyperpolarization of the action potential threshold normalized but membrane depolarization and attenuated divalent-dependent excitability persisted. CONCLUSIONS: Coronavirus-associated cytokine exposure increases spontaneous excitability in neocortical neurons, and some of the changes persist after cytokine removal. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-023-00557-9. |
format | Online Article Text |
id | pubmed-10575822 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-105758222023-10-15 Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation Rajayer, Salil R. Smith, Stephen M. Intensive Care Med Exp Research Articles BACKGROUND: Neurological manifestations of severe coronavirus infections, including SARS-CoV-2, are wide-ranging and may persist following virus clearance. Detailed understanding of the underlying changes in brain function may facilitate the identification of therapeutic targets. We directly tested how neocortical function is impacted by the specific panel of cytokines that occur in coronavirus brain infection. Using the whole-cell patch-clamp technique, we determined how the five cytokines (TNFα, IL-1β, IL-6, IL-12p40 and IL-15 for 22–28-h) at concentrations matched to those elicited by MHV-A59 coronavirus brain infection, affected neuronal function in cultured primary mouse neocortical neurons. RESULTS: We evaluated how acute cytokine exposure affected neuronal excitability (propensity to fire action potentials), membrane properties, and action potential characteristics, as well as sensitivity to changes in extracellular calcium and magnesium (divalent) concentration. Neurovirulent cytokines increased spontaneous excitability and response to low divalent concentration by depolarizing the resting membrane potential and hyperpolarizing the action potential threshold. Evoked excitability was also enhanced by neurovirulent cytokines at physiological divalent concentrations. At low divalent concentrations, the change in evoked excitability was attenuated. One hour after cytokine removal, spontaneous excitability and hyperpolarization of the action potential threshold normalized but membrane depolarization and attenuated divalent-dependent excitability persisted. CONCLUSIONS: Coronavirus-associated cytokine exposure increases spontaneous excitability in neocortical neurons, and some of the changes persist after cytokine removal. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-023-00557-9. Springer International Publishing 2023-10-14 /pmc/articles/PMC10575822/ /pubmed/37833408 http://dx.doi.org/10.1186/s40635-023-00557-9 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Articles Rajayer, Salil R. Smith, Stephen M. Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
title | Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
title_full | Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
title_fullStr | Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
title_full_unstemmed | Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
title_short | Neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
title_sort | neurovirulent cytokines increase neuronal excitability in a model of coronavirus-induced neuroinflammation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575822/ https://www.ncbi.nlm.nih.gov/pubmed/37833408 http://dx.doi.org/10.1186/s40635-023-00557-9 |
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