A proline-rich motif on VGLUT1 reduces synaptic vesicle super-pool and spontaneous release frequency

  1. Xiao Min Zhang
  2. Urielle François
  3. Kätlin Silm
  4. Maria Florencia Angelo
  5. Maria Victoria Fernandez-Busch
  6. Mona Maged
  7. Christelle Martin
  8. Véronique Bernard
  9. Fabrice P Cordelières
  10. Melissa Deshors
  11. Stéphanie Pons
  12. Uwe Maskos
  13. Alexis Pierre Bemelmans
  14. Sonja M Wojcik
  15. Salah El Mestikawy
  16. Yann Humeau
  17. Etienne Herzog  Is a corresponding author
  1. CNRS - Université de Bordeaux, France
  2. CNRS - INSERM - Université Pierre et Marie Curie, France
  3. Institut Pasteur, France
  4. CNRS, Université Paris-Sud, Université Paris-Saclay, France
  5. Max-Planck-Institut fuer Experimentelle Medizin, Germany

Abstract

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through the interaction of VGLUT1 second proline-rich domain, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between Src homology 3 and proline-rich domains of synaptic proteins. In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of SV organization and spontaneous release.

Data availability

Raw measures and intermediate data processing of images and electrophysiology traces are submited in source files appended to this submission.Source images and electrophysiology traces reported in this study are fully available upon request to the corresponding author (Etienne Herzog - https://orcid.org/0000-0002-0058-6959).

Article and author information

Author details

  1. Xiao Min Zhang

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Urielle François

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Kätlin Silm

    Neurosciences Paris Seine, CNRS - INSERM - Université Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Maria Florencia Angelo

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Maria Victoria Fernandez-Busch

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Mona Maged

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Christelle Martin

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Véronique Bernard

    Neurosciences Paris Seine, CNRS - INSERM - Université Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Fabrice P Cordelières

    Bordeaux Imaging Center, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5383-5816
  10. Melissa Deshors

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Stéphanie Pons

    Unité de Neurobiologie Intégrative des Systèmes Cholinergiques, Department of Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1027-0621
  12. Uwe Maskos

    Unité de Neurobiologie Intégrative des Systèmes Cholinergiques, Department of Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Alexis Pierre Bemelmans

    Neurodegenerative Diseases Laboratory, CNRS, Université Paris-Sud, Université Paris-Saclay, Fontenay-aux-Roses, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Sonja M Wojcik

    Department of Molecular Neurobiology, Max-Planck-Institut fuer Experimentelle Medizin, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Salah El Mestikawy

    Neurosciences Paris Seine, CNRS - INSERM - Université Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Yann Humeau

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  17. Etienne Herzog

    Interdisciplinary Institute for Neuroscience, CNRS - Université de Bordeaux, Bordeaux, France
    For correspondence
    etienne.herzog@u-bordeaux.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0058-6959

Funding

Agence Nationale de la Recherche (ANR-12-JSV4-0005-01 VGLUT-IQ)

  • Etienne Herzog

Agence Nationale de la Recherche (ANR-10-LABX-43 BRAIN)

  • Yann Humeau
  • Etienne Herzog

Agence Nationale de la Recherche (ANR-10-IDEX-03-02 PEPS SV-PIT)

  • Etienne Herzog

Agence Nationale de la Recherche (PSYVGLUT 09-MNPS-033)

  • Salah El Mestikawy

Agence Nationale de la Recherche (ANR-10-INBS-04)

  • Fabrice P Cordelières

European Commission (Erasmus-Mundus European Neuroscience Campus Program)

  • Xiao Min Zhang
  • Etienne Herzog

Fondation pour la Recherche Médicale (FDT20120925288)

  • Kätlin Silm

Fondation pour la Recherche Médicale (ING20150532192)

  • Maria Florencia Angelo

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

Ethics

Animal experimentation: The experimental design and all procedures were in accordance with the European guide for the care and use of laboratory animals, approved by the ethics committee of Bordeaux Universities (CE50), and registered with the french ministry for research under the APAFIS n{degree sign}1692. Every effort was made to minimize the number of animals used and their suffering.

Reviewing Editor

  1. Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany

Publication history

  1. Received: July 22, 2019
  2. Accepted: October 27, 2019
  3. Accepted Manuscript published: October 30, 2019 (version 1)
  4. Version of Record published: November 18, 2019 (version 2)

Copyright

© 2019, Zhang 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. Xiao Min Zhang
  2. Urielle François
  3. Kätlin Silm
  4. Maria Florencia Angelo
  5. Maria Victoria Fernandez-Busch
  6. Mona Maged
  7. Christelle Martin
  8. Véronique Bernard
  9. Fabrice P Cordelières
  10. Melissa Deshors
  11. Stéphanie Pons
  12. Uwe Maskos
  13. Alexis Pierre Bemelmans
  14. Sonja M Wojcik
  15. Salah El Mestikawy
  16. Yann Humeau
  17. Etienne Herzog
(2019)
A proline-rich motif on VGLUT1 reduces synaptic vesicle super-pool and spontaneous release frequency
eLife 8:e50401.
https://doi.org/10.7554/eLife.50401

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