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Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

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Cite this article as: eLife 2022;11:e72898 doi: 10.7554/eLife.72898

Abstract

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

Data availability

All data generated or analysed during this study are included in the manuscript and corresponding data tables. We have also deposited our raw datasets for each figure with Dryad are accessible at the following URL: https://doi.org/10.5061/dryad.zcrjdfncm.

The following data sets were generated

Article and author information

Author details

  1. Kathryn A Salvati

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    For correspondence
    kathryn.salvati@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. George MPR Souza

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam C Lu

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew L Ritger

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Patrice Guyenet

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephen B Abbott

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1244-3637
  7. Mark P Beenhakker

    Department of Pharmacology, University of Virginia, Charlottesville, United States
    For correspondence
    markbeen@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4541-0201

Funding

National Institute of Neurological Disorders and Stroke (R01NS099586)

  • Mark P Beenhakker

National Institute of Neurological Disorders and Stroke (R56NS099586)

  • Mark P Beenhakker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures conformed to the National Institutes of Health Guide for Care and Use ofLaboratory Animals and were approved by the University of Virginia Animal Care and UseCommittee (protocol #3892).

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: August 8, 2021
  2. Accepted: January 3, 2022
  3. Accepted Manuscript published: January 4, 2022 (version 1)

Copyright

© 2022, Salvati et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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