1. Neuroscience

Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing

  1. Colin M Cleary
  2. Brenda M Milla
  3. Fu-Shan Kuo
  4. Shaun James
  5. William F Flynn
  6. Paul Robson
  7. Daniel K Mulkey  Is a corresponding author
  1. University of Connecticut, United States
  2. The Jackson Laboratory, United States
https://doi.org/10.7554/eLife.60317
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Cite this article
  1. Colin M Cleary
  2. Brenda M Milla
  3. Fu-Shan Kuo
  4. Shaun James
  5. William F Flynn
  6. Paul Robson
  7. Daniel K Mulkey
(2021)
Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing
eLife 10:e60317.
https://doi.org/10.7554/eLife.60317
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Abstract

Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et. al., 2019; 25). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)- and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.

Data availability

Raw and processed scRNA-seq data are available through the Gene Expression Omnibus (accession GSE153172) and analysis code is available on GitHub. Analysis of FISH, electrophysiology, and respiratory activity data was done using standard software and no custom code was written.

The following data sets were generated

Article and author information

Author details

  1. Colin M Cleary

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0305-1324

  2. Brenda M Milla

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Fu-Shan Kuo

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Shaun James

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. William F Flynn

    Computational Sciences, The Jackson Laboratory, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6533-0340

  6. Paul Robson

    Computational Sciences, The Jackson Laboratory, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0191-3958

  7. Daniel K Mulkey

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    For correspondence
    daniel.mulkey@uconn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7040-3927

Funding

National Institutes of Health (HL104101)

  • Daniel K Mulkey

National Institutes of Health (HL137094)

  • Daniel K Mulkey

National Institutes of Health (NS099887)

  • Daniel K Mulkey

National Institutes of Health (HL142227)

  • Colin M Cleary

National Institutes of Health (F31NS120467)

  • Brenda M Milla

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

Reviewing Editor

  1. Muriel Thoby-Brisson, CNRS Université de Bordeaux, France

Ethics

Animal experimentation: All procedures were performed in accordance with National Institutes of Health and University of Connecticut Animal Care and Use Guidelines (protocols A19-048 and A20-016).

Version history

  1. Received: June 23, 2020
  2. Accepted: May 19, 2021
  3. Accepted Manuscript published: May 20, 2021 (version 1)
  4. Version of Record published: June 1, 2021 (version 2)

Copyright

© 2021, Cleary 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. Colin M Cleary
  2. Brenda M Milla
  3. Fu-Shan Kuo
  4. Shaun James
  5. William F Flynn
  6. Paul Robson
  7. Daniel K Mulkey
(2021)
Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing
eLife 10:e60317.
https://doi.org/10.7554/eLife.60317

Share this article

https://doi.org/10.7554/eLife.60317

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Further reading

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    Disordered breathing in a mouse model of Dravet syndrome

    Fu-Shan Kuo, Colin M Cleary ... Daniel K Mulkey
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    Dravet syndrome (DS) is a form of epilepsy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Respiratory failure is a leading cause of SUDEP, and DS patients’ frequently exhibit disordered breathing. Despite this, mechanisms underlying respiratory dysfunction in DS are unknown. We found that mice expressing a DS-associated Scn1a missense mutation (A1783V) conditionally in inhibitory neurons (Slc32a1cre/+::Scn1aA1783V fl/+; defined as Scn1aΔE26) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype including hypoventilation, apnea, and a diminished ventilatory response to CO2. At the cellular level in the retrotrapezoid nucleus (RTN), we found inhibitory neurons expressing the Scn1a A1783V variant are less excitable, whereas glutamatergic chemosensitive RTN neurons, which are a key source of the CO2/H+-dependent drive to breathe, are hyper-excitable in slices from Scn1aΔE26 mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.

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