1. Neuroscience
Download icon

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
Research Advance
  • Cited 14
  • Views 1,511
  • Annotations
Cite this article as: eLife 2017;6:e29566 doi: 10.7554/eLife.29566


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
    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


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.


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).

Reviewing Editor

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

Publication 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)


© 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.


  • 1,511
    Page views
  • 280
  • 14

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

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)

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

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

Further reading

    1. Neuroscience
    Kang-Ying Qian et al.
    Research Article Updated

    The development of functional synapses in the nervous system is important for animal physiology and behaviors, and its disturbance has been linked with many neurodevelopmental disorders. The synaptic transmission efficacy can be modulated by the environment to accommodate external changes, which is crucial for animal reproduction and survival. However, the underlying plasticity of synaptic transmission remains poorly understood. Here we show that in Caenorhabditis elegans, the male environment increases the hermaphrodite cholinergic transmission at the neuromuscular junction (NMJ), which alters hermaphrodites’ locomotion velocity and mating efficiency. We identify that the male-specific pheromones mediate this synaptic transmission modulation effect in a developmental stage-dependent manner. Dissection of the sensory circuits reveals that the AWB chemosensory neurons sense those male pheromones and further transduce the information to NMJ using cGMP signaling. Exposure of hermaphrodites to the male pheromones specifically increases the accumulation of presynaptic CaV2 calcium channels and clustering of postsynaptic acetylcholine receptors at cholinergic synapses of NMJ, which potentiates cholinergic synaptic transmission. Thus, our study demonstrates a circuit mechanism for synaptic modulation and behavioral flexibility by sexual dimorphic pheromones.

    1. Immunology and Inflammation
    2. Neuroscience
    Ibrahim T Mughrabi et al.
    Tools and Resources Updated

    Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in four research laboratories. We observed significant heart rate responses for at least 4 weeks in 60–90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice.