Excitatory and inhibitory receptors utilize distinct post- and trans-synaptic mechanisms in vivo

  1. Taisuke Miyazaki
  2. Megumi Morimoto-Tomita
  3. Coralie Berthoux
  4. Kotaro Konno
  5. Yoav Noam
  6. Tokiwa Yamasaki
  7. Matthijs Verhage
  8. Pablo E Castillo
  9. Masahiko Watanabe
  10. Susumu Tomita  Is a corresponding author
  1. Hokkaido University, Japan
  2. Yale University, United States
  3. Albert Einstein College of Medicine, United States
  4. Amsterdam University Medical Center, Netherlands

Abstract

Ionotropic neurotransmitter receptors at postsynapses mediate fast synaptic transmission upon binding of the neurotransmitter. Post- and trans-synaptic mechanisms through cytosolic, membrane, and secreted proteins have been proposed to localize neurotransmitter receptors at postsynapses. However, it remains unknown which mechanism is crucial to maintain neurotransmitter receptors at postsynapses. In this study, we ablated excitatory or inhibitory neurons in adult mouse brains in a cell-autonomous manner. Unexpectedly, we found that excitatory AMPA receptors remain at the postsynaptic density upon ablation of excitatory presynaptic terminals. In contrast, inhibitory GABAA receptors required inhibitory presynaptic terminals for their postsynaptic localization. Consistent with this finding, ectopic expression at excitatory presynapses of neurexin 3alpha, a putative trans-synaptic interactor with the native GABAA receptor complex, could recruit GABAA receptors to contacted postsynaptic sites. These results establish distinct mechanisms for the maintenance of excitatory and inhibitory postsynaptic receptors in the mature mammalian brain.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file. Source Data files showing all raw values for each figure and the original images of uncropped blots for Figure 6B have been provided.

Article and author information

Author details

  1. Taisuke Miyazaki

    Anatomy, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Megumi Morimoto-Tomita

    Cellular and Molecular Physiology, Neuroscience, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Coralie Berthoux

    Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kotaro Konno

    Department of Anatomy, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Yoav Noam

    Cellular and Molecular Physiology, Neuroscience, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tokiwa Yamasaki

    Cellular and Molecular Physiology, Neuroscience, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Matthijs Verhage

    Department of Clinical Genetics, Amsterdam University Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Pablo E Castillo

    Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9834-1801
  9. Masahiko Watanabe

    Department of Anatomy, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5037-7138
  10. Susumu Tomita

    Cellular and Molecular Physiology, Neuroscience, Yale University, New Haven, United States
    For correspondence
    susumu.tomita@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8344-259X

Funding

NIH Office of the Director (MH115705)

  • Susumu Tomita

NIH Office of the Director (MH077939)

  • Susumu Tomita

Grant-in-Aid for Scientific Research (MEXT 17K08485)

  • Taisuke Miyazaki

Grant-in-Aid for Scientific Research (MEXT 18K06813)

  • Taisuke Miyazaki

NIH Office of the Director (F32NS093952)

  • Yoav Noam

NIH Office of the Director (NS113600)

  • Pablo E Castillo

NIH Office of the Director (MH125772)

  • Pablo E Castillo

NIH Office of the Director (MH125772)

  • Pablo E Castillo

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

Ethics

Animal experimentation: All animal handling was in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Yale University (Animal Welfare Assurance# A3230-01, Animal protocol number 2021-11029), the Albert Einstein College of Medicine (Animal Welfare Assurance# A3312-011, Animal protocol number 00001043) and Hokkaido University, Japan (Approval number, #19-0111). Animal care and housing were provided by the Yale Animal Resource Center (YARC), in compliance with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996).

Reviewing Editor

  1. Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Republic of Korea

Publication history

  1. Received: June 3, 2020
  2. Accepted: September 19, 2021
  3. Accepted Manuscript published: October 18, 2021 (version 1)
  4. Version of Record published: October 27, 2021 (version 2)

Copyright

© 2021, Miyazaki 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. Taisuke Miyazaki
  2. Megumi Morimoto-Tomita
  3. Coralie Berthoux
  4. Kotaro Konno
  5. Yoav Noam
  6. Tokiwa Yamasaki
  7. Matthijs Verhage
  8. Pablo E Castillo
  9. Masahiko Watanabe
  10. Susumu Tomita
(2021)
Excitatory and inhibitory receptors utilize distinct post- and trans-synaptic mechanisms in vivo
eLife 10:e59613.
https://doi.org/10.7554/eLife.59613
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