Endothelin signalling mediates experience-dependent myelination in the CNS

  1. Matthew Swire  Is a corresponding author
  2. Yuri Kotelevtsev
  3. David J Webb
  4. David A Lyons
  5. Charles ffrench-Constant
  1. University of Edinburgh, United Kingdom
  2. Skoltech Institute for Science and Technology, Russian Federation

Abstract

Experience and changes in neuronal activity can alter CNS myelination, but the signalling pathways responsible remain poorly understood. Here we define a pathway in which endothelin, signalling through the G protein-coupled receptor endothelin receptor B and PKC epsilon, regulates the number of myelin sheaths formed by individual oligodendrocytes in mouse and zebrafish. We show that this phenotype is also observed in the prefrontal cortex of mice following social isolation, and is associated with reduced expression of vascular endothelin. Additionally, we show that increasing endothelin signalling rescues this myelination defect caused by social isolation. Together, these results indicate that the vasculature responds to changes in neuronal activity associated with experience by regulating endothelin levels, which in turn affect the myelinating capacity of oligodendrocytes. This pathway may be employed to couple the metabolic support function of myelin to activity-dependent demand and also represents a novel mechanism for adaptive myelination.

Data availability

Data generated from phosphorylation screen is included in supporting files - supplementary file 1

Article and author information

Author details

  1. Matthew Swire

    MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    mswire@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4294-4926
  2. Yuri Kotelevtsev

    Centre for Neurobiology and Brain Restoration, Skoltech Institute for Science and Technology, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  3. David J Webb

    British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. David A Lyons

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1166-4454
  5. Charles ffrench-Constant

    MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Funding

Wellcome

  • Charles ffrench-Constant

Multiple Sclerosis Society (950)

  • Charles ffrench-Constant

Wellcome (102836/Z/13/Z)

  • David A Lyons

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

Ethics

Animal experimentation: Animal husbandry and experiments were performed under UK Home Office project licenses issued under the Animals (Scientific Procedures) Act, under project licences 60/8436, 70/8436 and 70/8748. All animal experiments were reviewed, revised and approved by the University of Edinburgh Bioresearch & Veterinary Services team.

Copyright

© 2019, Swire 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

  • 3,497
    views
  • 531
    downloads
  • 73
    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. Matthew Swire
  2. Yuri Kotelevtsev
  3. David J Webb
  4. David A Lyons
  5. Charles ffrench-Constant
(2019)
Endothelin signalling mediates experience-dependent myelination in the CNS
eLife 8:e49493.
https://doi.org/10.7554/eLife.49493

Share this article

https://doi.org/10.7554/eLife.49493

Further reading

    1. Neuroscience
    Philipp S O'Neill, Martín Baccino-Calace ... Igor Delvendahl
    Tools and Resources

    Quantitative information about synaptic transmission is key to our understanding of neural function. Spontaneously occurring synaptic events carry fundamental information about synaptic function and plasticity. However, their stochastic nature and low signal-to-noise ratio present major challenges for the reliable and consistent analysis. Here, we introduce miniML, a supervised deep learning-based method for accurate classification and automated detection of spontaneous synaptic events. Comparative analysis using simulated ground-truth data shows that miniML outperforms existing event analysis methods in terms of both precision and recall. miniML enables precise detection and quantification of synaptic events in electrophysiological recordings. We demonstrate that the deep learning approach generalizes easily to diverse synaptic preparations, different electrophysiological and optical recording techniques, and across animal species. miniML provides not only a comprehensive and robust framework for automated, reliable, and standardized analysis of synaptic events, but also opens new avenues for high-throughput investigations of neural function and dysfunction.

    1. Neuroscience
    Maxine K Loh, Samantha J Hurh ... Mitchell F Roitman
    Research Article

    Mesolimbic dopamine encoding of non-contingent rewards and reward-predictive cues has been well established. Considerable debate remains over how mesolimbic dopamine responds to aversion and in the context of aversive conditioning. Inconsistencies may arise from the use of aversive stimuli that are transduced along different neural paths relative to reward or the conflation of responses to avoidance and aversion. Here, we made intraoral infusions of sucrose and measured how dopamine and behavioral responses varied to the changing valence of sucrose. Pairing intraoral sucrose with malaise via injection of lithium chloride (LiCl) caused the development of a conditioned taste aversion (CTA), which rendered the typically rewarding taste of sucrose aversive upon subsequent re-exposure. Following CTA formation, intraoral sucrose suppressed the activity of ventral tegmental area dopamine neurons (VTADA) and nucleus accumbens (NAc) dopamine release. This pattern of dopamine signaling after CTA is similar to intraoral infusions of innately aversive quinine and contrasts with responses to sucrose when it was novel or not paired with LiCl. Dopamine responses were negatively correlated with behavioral reactivity to intraoral sucrose and predicted home cage sucrose preference. Further, dopamine responses scaled with the strength of the CTA, which was increased by repeated LiCl pairings and weakened through extinction. Thus, the findings demonstrate differential dopamine encoding of the same taste stimulus according to its valence, which is aligned to distinct behavioral responses.