The role of P2Y12 in the kinetics of microglial self-renewal and maturation in the adult visual cortex in vivo

Abstract

Microglia are the brain's resident immune cells with a tremendous capacity to autonomously self-renew. Because microglial self-renewal has largely been studied using static tools, its mechanisms and kinetics are not well understood. Using chronic in vivo two-photon imaging in awake mice, we confirm that cortical microglia show limited turnover and migration under basal conditions. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of remaining microglia, in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia within days of repopulation, although morphological maturation is different in newly born microglia in P2Y12 knock out mice. Our work suggests that microglia rapidly locally and that newly-born microglia do not recapitulate the slow maturation seen in development but instead take on mature roles in the CNS.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Monique Mendes

    Neuroscience, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9800-5923
  2. Linh Le

    Neuroscience, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jason Atlas

    Neuroscience, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zachary Brehm

    Biostatistics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Antonio Ladron-de-Guevara

    Biomedical Engineering, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1093-2509
  6. Evelyn Matei

    Neuroscience, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Cassandra Lamantia

    Biomedical Engineering, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Matthew McCall

    Biostatistics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ania K Majewska

    Biomedical Engineering, University of Rochester Medical Center, Rochester, United States
    For correspondence
    ania_majewska@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2167-6849

Funding

NIH Blueprint for Neuroscience Research (F99 NS108486-02)

  • Monique Mendes

National Institute of Neurological Disorders and Stroke (R01 EY019277)

  • Ania K Majewska

National Institute of Neurological Disorders and Stroke (RO1 NS114480)

  • Ania K Majewska

National Institute of Neurological Disorders and Stroke (R21 NS099973)

  • Ania K Majewska

National Science Foundation (1557971)

  • Ania K Majewska

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 Experiments: All animal work was performed according to the approved guidelines from the University of Rochester, Institutional Animal Care and Use Committee and conformed to the National Institute of Health (NIH). Animals were housed in a 12-hour light/12-hour dark cycle with food ad libitum. Mice were housed in cages on a standard 12:12 hour light/dark cycle with food and water ad libitum. All animal experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Ethical approval number: UCAR: 2008-111; expires Dec. 1, 2023.

Reviewing Editor

  1. Sonia Garel, Ecole Normale Superieure, France

Publication history

  1. Preprint posted: March 6, 2020 (view preprint)
  2. Received: July 16, 2020
  3. Accepted: July 10, 2021
  4. Accepted Manuscript published: July 12, 2021 (version 1)
  5. Version of Record published: August 5, 2021 (version 2)

Copyright

© 2021, Mendes 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. Monique Mendes
  2. Linh Le
  3. Jason Atlas
  4. Zachary Brehm
  5. Antonio Ladron-de-Guevara
  6. Evelyn Matei
  7. Cassandra Lamantia
  8. Matthew McCall
  9. Ania K Majewska
(2021)
The role of P2Y12 in the kinetics of microglial self-renewal and maturation in the adult visual cortex in vivo
eLife 10:e61173.
https://doi.org/10.7554/eLife.61173

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