Local axonal morphology guides the topography of interneuron myelination in mouse and human neocortex

Abstract

GABAergic fast-spiking parvalbumin-positive (PV) interneurons are frequently myelinated in the cerebral cortex. However, the factors governing the topography of cortical interneuron myelination remain incompletely understood. Here, we report that segmental myelination along neocortical interneuron axons is strongly predicted by the joint combination of interbranch distance and local axon caliber. Enlargement of PV+ interneurons increased axonal myelination, while reduced cell size led to decreased myelination. Next, we considered regular-spiking SOM+ cells, which normally have relatively shorter interbranch distances and thinner axon diameters than PV+ cells, and are rarely myelinated. Consistent with the importance of axonal morphology for guiding interneuron myelination, enlargement of SOM+ cell size dramatically increased the frequency of myelinated axonal segments. Lastly, we confirm that these findings also extend to human neocortex by quantifying interneuron axonal myelination from ex vivo surgical tissue. Together, these findings establish a predictive model of neocortical GABAergic interneuron myelination determined by local axonal morphology.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-9. Fiji ImageJ code for semi-automated reconstruction of axon diameter has been provided as an additional file. Human and mouse PV cell reconstructions will be uploaded to NeuroMorpho (http://neuromorpho.org/).

Article and author information

Author details

  1. Jeffrey Stedehouder

    Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Demi Brizee

    Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Johan A Slotman

    Erasmus Optical Imaging Centre, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9705-9620
  4. Maria Pascual-Garcia

    Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Megan L Leyrer

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5670-4005
  6. Bibi LJ Bouwen

    Department of Neuroscience, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Clemens MF Dirven

    Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Zhenyu Gao

    Department of Neuroscience, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4979-2366
  9. David M Berson

    Department of Neuroscience, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Adriaan B Houtsmuller

    Erasmus Optical Imaging Centre, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Steven A Kushner

    Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands
    For correspondence
    s.kushner@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9777-3338

Funding

Horizon 2020 Framework Programme (NEURON-JTC2018-024)

  • Steven A Kushner

ZonMw (40-00812-98-15030)

  • Steven A Kushner

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (834.12.002)

  • Steven A Kushner

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (IG 15-064) of the Dutch Ethical Committee (DEC). The protocol was approved by the Netherlands Centrale Commissie Dierproeven (Permit Number: AVD1010020173544). All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Human subjects: All procedures regarding human tissue were performed with the approval of the Medical Ethical Committee of the Erasmus University Medical Center. Written informed consent of each patient was provided in accordance with the Helsinki Declaration.

Copyright

© 2019, Stedehouder 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. Jeffrey Stedehouder
  2. Demi Brizee
  3. Johan A Slotman
  4. Maria Pascual-Garcia
  5. Megan L Leyrer
  6. Bibi LJ Bouwen
  7. Clemens MF Dirven
  8. Zhenyu Gao
  9. David M Berson
  10. Adriaan B Houtsmuller
  11. Steven A Kushner
(2019)
Local axonal morphology guides the topography of interneuron myelination in mouse and human neocortex
eLife 8:e48615.
https://doi.org/10.7554/eLife.48615

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https://doi.org/10.7554/eLife.48615

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