Brain-specific Drp1 regulates postsynaptic endocytosis and dendrite formation independently of mitochondrial division

Abstract

Dynamin-related protein 1 (Drp1) divides mitochondria as a mechano-chemical GTPase. However, the function of Drp1 beyond mitochondrial division is largely unknown. Multiple Drp1 isoforms are produced through mRNA splicing. One such isoform, Drp1ABCD, contains all four alternative exons and is specifically expressed in the brain. Here, we studied the function of Drp1ABCD in mouse neurons in both culture and animal systems using isoform-specific knockdown by shRNA and isoform-specific knockout by CRISPR/Cas9. We found that the expression of Drp1ABCD is induced during postnatal brain development. Drp1ABCD is enriched in dendritic spines and regulates postsynaptic clathrin-mediated endocytosis by positioning the endocytic zone at the postsynaptic density, independently of mitochondrial division. Drp1ABCD loss promotes the formation of ectopic dendrites in neurons and enhanced sensorimotor gating behavior in mice. These data reveal that Drp1ABCD controls postsynaptic endocytosis, neuronal morphology and brain function.

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

Article and author information

Author details

  1. Kie Itoh

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daisuke Murata

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Takashi Kato

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tatsuya Yamada

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yoichi Araki

    Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Atsushi Saito

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yoshihiro Adachi

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Atsushi Igarashi

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Shuo Li

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Mikhail Pletnikov

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Richard L Huganir

    Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Shigeki Watanabe

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Atsushi Kamiya

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Miho Iijima

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    miijima@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
  15. Hiromi Sesaki

    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    hsesaki@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6877-3929

Funding

National Institute of General Medical Sciences (GM131768)

  • Miho Iijima

National Institute of General Medical Sciences (GM123266)

  • Hiromi Sesaki

National Institute of General Medical Sciences (GM130695)

  • Hiromi Sesaki

National Institute on Drug Abuse (DA041208)

  • Mikhail Pletnikov
  • Atsushi Kamiya

National Institute of Mental Health (MH083728)

  • Mikhail Pletnikov

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 animal work was conducted according to the guidelines established by the Johns Hopkins University Committee on Animal Care and Use. The protocol (MO17M181) has been approved by the same committee.

Reviewing Editor

  1. Margaret S Robinson, University of Cambridge, United Kingdom

Publication history

  1. Received: December 27, 2018
  2. Accepted: October 10, 2019
  3. Accepted Manuscript published: October 11, 2019 (version 1)
  4. Accepted Manuscript updated: October 16, 2019 (version 2)
  5. Version of Record published: November 1, 2019 (version 3)

Copyright

© 2019, Itoh 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. Kie Itoh
  2. Daisuke Murata
  3. Takashi Kato
  4. Tatsuya Yamada
  5. Yoichi Araki
  6. Atsushi Saito
  7. Yoshihiro Adachi
  8. Atsushi Igarashi
  9. Shuo Li
  10. Mikhail Pletnikov
  11. Richard L Huganir
  12. Shigeki Watanabe
  13. Atsushi Kamiya
  14. Miho Iijima
  15. Hiromi Sesaki
(2019)
Brain-specific Drp1 regulates postsynaptic endocytosis and dendrite formation independently of mitochondrial division
eLife 8:e44739.
https://doi.org/10.7554/eLife.44739

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