1. Neuroscience

Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe

  1. Virginia E Hawkins
  2. Ana C Takakura
  3. Ashley Trinh
  4. Milene R Malheiros-Lima
  5. Colin M Cleary
  6. Ian C Wenker
  7. Todd Dubreuil
  8. Elliot M Rodriguez
  9. Mark T Nelson
  10. Thiago S Moreira  Is a corresponding author
  11. Daniel K Mulkey  Is a corresponding author
  1. University of Connecticut, United States
  2. University of São Paulo, Brazil
  3. College of Medicine, University of Vermont, United States
https://doi.org/10.7554/eLife.25232
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Cite this article
  1. Virginia E Hawkins
  2. Ana C Takakura
  3. Ashley Trinh
  4. Milene R Malheiros-Lima
  5. Colin M Cleary
  6. Ian C Wenker
  7. Todd Dubreuil
  8. Elliot M Rodriguez
  9. Mark T Nelson
  10. Thiago S Moreira
  11. Daniel K Mulkey
(2017)
Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe
eLife 6:e25232.
https://doi.org/10.7554/eLife.25232
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  3. Download .RIS

Abstract

Cerebral blood flow is highly sensitive to changes in CO2/H+ where an increase in CO2/H+ causes vasodilation and increased blood flow. Tissue CO2/H+ also functions as the main stimulus for breathing by activating chemosensitive neurons that control respiratory output. Considering that CO2/H+-induced vasodilation would accelerate removal of CO2/H+ and potentially counteract the drive to breathe, we hypothesize that chemosensitive brain regions have adapted a means of preventing vascular CO2/H+-reactivity. Here, we show in rat that purinergic signaling, possibly through P2Y2/4 receptors, in the retrotrapezoid nucleus (RTN) maintains arteriole tone during high CO2/H+ and disruption of this mechanism decreases the CO2ventilatory response. Our discovery that CO2/H+-dependent regulation of vascular tone in the RTN is the opposite to the rest of the cerebral vascular tree is novel and fundamentally important for understanding how regulation of vascular tone is tailored to support neural function and behavior, in this case the drive to breathe.

Article and author information

Author details

  1. Virginia E Hawkins

    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:" 0000-0001-9505-6776

  2. Ana C Takakura

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  3. Ashley Trinh

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

  4. Milene R Malheiros-Lima

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  5. Colin M Cleary

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

  6. Ian C Wenker

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

  7. Todd Dubreuil

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

  8. Elliot M Rodriguez

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

  9. Mark T Nelson

    Department Pharmacology, College of Medicine, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Thiago S Moreira

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    For correspondence
    tmoreira@icb.usp.br
    Competing interests
    The authors declare that no competing interests exist.

  11. 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 (DK053832)

  • Mark T Nelson

National Institutes of Health (HL131181)

  • Mark T Nelson

Sao Paulo Research Foundation (2016/22069-0)

  • Thiago S Moreira

Sao Paulo Research Foundation (2015/23376-1)

  • Thiago S Moreira

Sao Paulo Research Foundation (2014/07698-6)

  • Milene R Malheiros-Lima

Conselho Nacional de Desenvolvimento Científico e Tecnológico (471283/2012-6)

  • Thiago S Moreira

Conselho Nacional de Desenvolvimento Científico e Tecnológico (301651/2013-2)

  • Ana C Takakura

Conselho Nacional de Desenvolvimento Científico e Tecnológico (301904/2015-4)

  • Thiago S Moreira

Totman Medical Research Trust

  • Mark T Nelson

Fondation Leducq

  • Mark T Nelson

EC horizon 2020

  • Mark T Nelson

Connecticut department of public health (150263)

  • Daniel K Mulkey

Sao Paulo Research Foundation (2014/22406-1)

  • Ana C Takakura

Conselho Nacional de Desenvolvimento Científico e Tecnológico (471263/2013-3)

  • Ana C Takakura

National Institutes of Health (HL126381)

  • Virginia E Hawkins

National Institutes of Health (HL095488)

  • Mark T Nelson

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 in vitro procedures were performed in accordance with National Institutes of Health and University of Connecticut Animal Care and Use Guidelines (protocol # A16-034). All in vivo procedures were performed in accordance with guidelines approved by the University of São Paulo Animal Care and Use Committee (protocol # 112/2015).

Copyright

© 2017, Hawkins 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. Virginia E Hawkins
  2. Ana C Takakura
  3. Ashley Trinh
  4. Milene R Malheiros-Lima
  5. Colin M Cleary
  6. Ian C Wenker
  7. Todd Dubreuil
  8. Elliot M Rodriguez
  9. Mark T Nelson
  10. Thiago S Moreira
  11. Daniel K Mulkey
(2017)
Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe
eLife 6:e25232.
https://doi.org/10.7554/eLife.25232

Share this article

https://doi.org/10.7554/eLife.25232

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Further reading

    1. Neuroscience

    Vascular control of the CO2/H+-dependent drive to breathe

    Colin M Cleary, Thiago S Moreira ... Daniel K Mulkey
    Research Advance Updated

    Respiratory chemoreceptors regulate breathing in response to changes in tissue CO2/H+. Blood flow is a fundamental determinant of tissue CO2/H+, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO2/H+-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al., 2017). Here, we show in mice that CO2/H+ dilates arterioles in other chemoreceptor regions, thus demonstrating CO2/H+ vascular reactivity in the RTN is unique. We also identify P2Y2 receptors in RTN smooth muscle cells as the substrate responsible for this response. Specifically, pharmacological blockade or genetic deletion of P2Y2 from smooth muscle cells blunted the ventilatory response to CO2, and re-expression of P2Y2 receptors only in RTN smooth muscle cells fully rescued the CO2/H+ chemoreflex. These results identify P2Y2 receptors in RTN smooth muscle cells as requisite determinants of respiratory chemoreception.

    1. Neuroscience

    Chemoreception: Keeping carbon dioxide in check

    Alfredo J Garcia III, Jan-Marino Ramirez
    Insight

    The response of the brainstem to increased levels of carbon dioxide in the blood is coordinated with the response of the cardiovascular system.

    1. Neuroscience
    2. Structural Biology and Molecular Biophysics

    Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons

    Amy N Shore, Keyong Li ... Matthew C Weston
    Research Article

    More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.