GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals

  1. Pradeep Bhandari
  2. David Vandael
  3. Diego Fernández-Fernández
  4. Thorsten Fritzius
  5. David Kleindienst
  6. Cihan Önal
  7. Jacqueline Montanaro
  8. Martin Gassmann
  9. Peter Jonas
  10. Akos Kulik
  11. Bernhard Bettler
  12. Ryuichi Shigemoto  Is a corresponding author
  13. Peter Koppensteiner  Is a corresponding author
  1. Institute of Science and Technology Austria, Austria
  2. University of Basel, Switzerland
  3. University of Freiburg, Germany

Abstract

The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors, and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.

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Article and author information

Author details

  1. Pradeep Bhandari

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  2. David Vandael

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  3. Diego Fernández-Fernández

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1431-3705
  4. Thorsten Fritzius

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. David Kleindienst

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  6. Cihan Önal

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2771-2011
  7. Jacqueline Montanaro

    IST Austria, Institute of Science and Technology Austria, Klosterneuburg,, Austria
    Competing interests
    The authors declare that no competing interests exist.
  8. Martin Gassmann

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Peter Jonas

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5001-4804
  10. Akos Kulik

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Bernhard Bettler

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  12. Ryuichi Shigemoto

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    For correspondence
    ryuichi.shigemoto@ist.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8761-9444
  13. Peter Koppensteiner

    Neuroscience, Institute of Science and Technology Austria, Klosterneuburg, Austria
    For correspondence
    peter.koppensteiner@ist.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3509-1948

Funding

H2020 European Research Council (694539)

  • Ryuichi Shigemoto

H2020 European Research Council (692692)

  • Peter Jonas

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A‐172881)

  • Bernhard Bettler

H2020 Marie Skłodowska-Curie Actions (665385)

  • Cihan Önal

Deutsche Forschungsgemeinschaft (For2143)

  • Akos Kulik

Deutsche Forschungsgemeinschaft (BIOSS-2)

  • Akos Kulik

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 experiments were performed in accordance with the license approved by the Austrian Federal Ministry of Science and Research (Animal license number: BMWFW-66.018/0012-WF/V/3b/2016) and the Austrian and EU animal laws.

Reviewing Editor

  1. Yukiko Goda, RIKEN, Japan

Publication history

  1. Received: March 10, 2021
  2. Accepted: April 28, 2021
  3. Accepted Manuscript published: April 29, 2021 (version 1)
  4. Version of Record published: May 14, 2021 (version 2)

Copyright

© 2021, Bhandari 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. Pradeep Bhandari
  2. David Vandael
  3. Diego Fernández-Fernández
  4. Thorsten Fritzius
  5. David Kleindienst
  6. Cihan Önal
  7. Jacqueline Montanaro
  8. Martin Gassmann
  9. Peter Jonas
  10. Akos Kulik
  11. Bernhard Bettler
  12. Ryuichi Shigemoto
  13. Peter Koppensteiner
(2021)
GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals
eLife 10:e68274.
https://doi.org/10.7554/eLife.68274

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