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

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.

Reviewing Editor

  1. Jan-Marino Ramirez, Seattle Children's Research Institute and University of Washington, United States

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).

Version history

  1. Received: June 19, 2017
  2. Accepted: October 3, 2017
  3. Accepted Manuscript published: October 4, 2017 (version 1)
  4. Version of Record published: October 19, 2017 (version 2)

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.

Metrics

  • 1,784
    views
  • 297
    downloads
  • 35
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Neuroscience
    Amanda Chu, Nicholas T Gordon ... Michael A McDannald
    Research Article

    Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior theoretically linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is theoretically linked to imminent or occurring predation. A criticism of studies observing fear conditioned cue-elicited locomotion is that responding is non-associative. We gave rats Pavlovian fear discrimination over a baseline of reward seeking. TTL-triggered cameras captured 5 behavior frames/s around cue presentation. Experiment 1 examined the emergence of danger-specific behaviors over fear acquisition. Experiment 2 examined the expression of danger-specific behaviors in fear extinction. In total, we scored 112,000 frames for nine discrete behavior categories. Temporal ethograms show that during acquisition, a fear conditioned cue suppresses reward seeking and elicits freezing, but also elicits locomotion, jumping, and rearing - all of which are maximal when foot shock is imminent. During extinction, a fear conditioned cue most prominently suppresses reward seeking, and elicits locomotion that is timed to shock delivery. The independent expression of these behaviors in both experiments reveal a fear conditioned cue to orchestrate a temporally organized suite of behaviors.

    1. Neuroscience
    Salima Messaoudi, Ada Allam ... Isabelle Caille
    Research Article

    The fragile X syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of autism spectrum disorder. FXS results from the absence of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal rostral migratory stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary Fmrp mRNA target implicated in these migratory defects is microtubule-associated protein 1B (MAP1B). Knocking down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.