Gasotransmitter modulation of hypoglossal motoneuron activity

Abstract

Obstructive sleep apnea (OSA) is characterized by sporadic collapse of the upper airway leading to periodic disruptions in breathing. Upper airway patency is governed by genioglossal nerve activity that originates from the hypoglossal motor nucleus. Mice with targeted deletion of the gene Hmox2, encoding the carbon monoxide (CO) producing enzyme, heme oxygenase-2 (HO-2), exhibit OSA, yet the contribution of central HO-2 dysregulation to the phenomenon is unknown. Using the rhythmic brainstem slice preparation that contains the preBötzinger complex (preBötC) and the hypoglossal nucleus, we tested the hypothesis that central HO-2 dysregulation weakens hypoglossal motoneuron output. Disrupting HO-2 activity increased the occurrence of subnetwork activity from the preBötC, which was associated with an increased irregularity of rhythmogenesis. These phenomena were also associated with the intermittent inability of the preBötC rhythm to drive output from the hypoglossal nucleus (i.e., transmission failures), and a reduction in the input-output relationship between the preBötC and the motor nucleus. HO-2 dysregulation reduced excitatory synaptic currents and intrinsic excitability in inspiratory hypoglossal neurons. Inhibiting activity of the CO-regulated H2S producing enzyme, cystathionine-g-lyase (CSE), reduced transmission failures in HO-2 null brainstem slices, which also normalized excitatory synaptic currents and intrinsic excitability of hypoglossal motoneurons. These findings demonstrate a hitherto uncharacterized modulation of hypoglossal activity through mutual interaction of HO‑2/CO and CSE/H2S, and support the potential importance of centrally‑derived gasotransmitter activity in regulating upper airway control.

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Article and author information

Author details

  1. Brigitte M Browe

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ying-Jie Peng

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jayasri Nanduri

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nanduri R Prabhakar

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alfredo J Garcia III

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    For correspondence
    ajgarcia3@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5620-7519

Funding

National Heart, Lung, and Blood Institute (P01 HL144454)

  • Nanduri R Prabhakar

National Institute of Neurological Disorders and Stroke (R01NS107421)

  • Alfredo J Garcia III

National Institute on Drug Abuse (R01DA057767)

  • Alfredo J Garcia III

National Heart, Lung, and Blood Institute (R01HL163965)

  • Alfredo J Garcia III

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

Ethics

Animal experimentation: In accordance with National Institutes of Health guidelines, all animal protocols were performed with the approval of the Institute of Animal Care and Use Committee at The University of Chicago (ACUP 72486, ACUP 71811).

Reviewing Editor

  1. Melissa Bates, University of Iowa, United States

Publication history

  1. Received: July 19, 2022
  2. Accepted: January 18, 2023
  3. Accepted Manuscript published: January 19, 2023 (version 1)

Copyright

© 2023, Browe 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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  1. Brigitte M Browe
  2. Ying-Jie Peng
  3. Jayasri Nanduri
  4. Nanduri R Prabhakar
  5. Alfredo J Garcia III
(2023)
Gasotransmitter modulation of hypoglossal motoneuron activity
eLife 12:e81978.
https://doi.org/10.7554/eLife.81978

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