1. Neuroscience

Astrocytes release prostaglandin E2 to modify respiratory network activity

  1. David Forsberg  Is a corresponding author
  2. Thomas Ringstedt
  3. Eric Herlenius
  1. Karolinska Institutet, Sweden
https://doi.org/10.7554/eLife.29566
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  1. David Forsberg
  2. Thomas Ringstedt
  3. Eric Herlenius
(2017)
Astrocytes release prostaglandin E2 to modify respiratory network activity
eLife 6:e29566.
https://doi.org/10.7554/eLife.29566
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Abstract

Previously (Forsberg et al., 2016), we revealed that prostaglandin E2 (PGE2), released during hypercapnic challenge, increases calcium oscillations in the chemosensitive parafacial respiratory group (pFRG/RTN). Here, we demonstrate that pFRG/RTN astrocytes are the PGE2 source. Two distinct astrocyte subtypes were found using transgenic mice expressing GFP and MrgA1 receptors in astrocytes. Although most astrocytes appeared dormant during time-lapse calcium imaging, a subgroup displayed persistent, rhythmic oscillating calcium activity. These active astrocytes formed a subnetwork within the respiratory network distinct from the neuronal network. Activation of exogenous MrgA1Rs expressed in astrocytes tripled astrocytic calcium oscillation frequency in both the preBötzinger complex and pFRG/RTN. However, neurons in the preBötC were unaffected, whereas neuronal calcium oscillatory frequency in pFRG/RTN doubled. Notably, astrocyte activation in pFRG/RTN triggered local PGE2 release and blunted the hypercapnic response. Thus, astrocytes play an active role in respiratory rhythm modulation, modifying respiratory-related behavior through PGE2 release in the pFRG/RTN.

Article and author information

Author details

  1. David Forsberg

    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
    For correspondence
    david.forsberg@ki.se
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4719-2201

  2. Thomas Ringstedt

    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    No competing interests declared.

  3. Eric Herlenius

    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    Eric Herlenius, employed at the Karolinska Institutet and the Karolinska University Hospital and is a coinventor of a patent application regarding biomarkers and their relation to breathing disorders, WO2009063226..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6859-0620

Funding

Karolinska Institutet

  • David Forsberg
  • Eric Herlenius

Swedish Research Council (EH 2016-01111)

  • Eric Herlenius

Hjärnfonden (EH FO2017-0203)

  • Eric Herlenius

M & M Wallenberg Foundation (EH 102179)

  • Eric Herlenius

Stockholms Läns Landsting (EH 20140011)

  • Eric Herlenius

Freemasons Children's House

  • David Forsberg
  • Eric Herlenius

Swedish National Heart and Lung Foundation (20150558)

  • Eric Herlenius

Swedish National Heart and Lung Foundation (20160549)

  • David Forsberg

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

Ethics

Animal experimentation: The studies were performed in strict accordance with European Community Guidelines and protocols approved by the regional ethic committee (Permit numbers: N247/13 and N265/14b).

Copyright

© 2017, Forsberg 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. David Forsberg
  2. Thomas Ringstedt
  3. Eric Herlenius
(2017)
Astrocytes release prostaglandin E2 to modify respiratory network activity
eLife 6:e29566.
https://doi.org/10.7554/eLife.29566

Share this article

https://doi.org/10.7554/eLife.29566

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Further reading

    1. Computational and Systems Biology
    2. Neuroscience

    CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture

    David Forsberg, Zachi Horn ... Eric Herlenius
    Research Article Updated

    Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R+/+ cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.