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).

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.

Metrics

  • 2,622
    views
  • 397
    downloads
  • 8
    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. 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

Share this article

https://doi.org/10.7554/eLife.59613

Further reading

    1. Neuroscience
    Ana Maria Ichim, Harald Barzan ... Raul Cristian Muresan
    Review Article

    Gamma oscillations in brain activity (30–150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a ‘servicing’ rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.

    1. Medicine
    2. Neuroscience
    LeYuan Gu, WeiHui Shao ... HongHai Zhang
    Research Article

    The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.