1. Neuroscience
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Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances

  1. Janus R L Kobbersmed
  2. Andreas T Grasskamp
  3. Meida Jusyte
  4. Mathias A Böhme
  5. Susanne Ditlevsen
  6. Jakob Balslev Sørensen
  7. Alexander M Walter  Is a corresponding author
  1. University of Copenhagen, Denmark
  2. Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany
Research Article
  • Cited 3
  • Views 2,160
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Cite this article as: eLife 2020;9:e51032 doi: 10.7554/eLife.51032

Abstract

Chemical synaptic transmission relies on the Ca2+-induced fusion of transmitter-laden vesicles whose coupling distance to Ca2+-channels determines synaptic release probability and short-term plasticity, the facilitation or depression of repetitive responses. Here, using electron- and super-resolution microscopy at the Drosophila neuromuscular junction we quantitatively map vesicle:Ca2+-channel coupling distances. These are very heterogeneous, resulting in a broad spectrum of vesicular release probabilities within synapses. Stochastic simulations of transmitter release from vesicles placed according to this distribution revealed strong constraints on short-term plasticity; particularly facilitation was difficult to achieve. We show that postulated facilitation mechanisms operating via activity-dependent changes of vesicular release probability (e.g. by a facilitation fusion sensor) generate too little facilitation and too much variance. In contrast, Ca2+-dependent mechanisms rapidly increasing the number of releasable vesicles reliably reproduce short-term plasticity and variance of synaptic responses. We propose activity-dependent inhibition of vesicle un-priming or release site activation as novel facilitation mechanisms.

Data availability

All data and software codes generated and used during this study are included in the manuscript and supporting files. Source data is included for all figures.

Article and author information

Author details

  1. Janus R L Kobbersmed

    Mathematical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0313-6205
  2. Andreas T Grasskamp

    Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5895-6529
  3. Meida Jusyte

    Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Mathias A Böhme

    Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0947-9172
  5. Susanne Ditlevsen

    Mathematical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1998-2783
  6. Jakob Balslev Sørensen

    Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5465-3769
  7. Alexander M Walter

    Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    For correspondence
    awalter@fmp-berlin.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5646-4750

Funding

Deutsche Forschungsgemeinschaft (Emmy Noether Programme)

  • Alexander M Walter

Deutsche Forschungsgemeinschaft (Project Number 278001972 - TRR 186)

  • Alexander M Walter

Independent Research Fund Denmark (Pregraduate scholarship (8141-00007B))

  • Jakob Balslev Sørensen

Deutsche Forschungsgemeinschaft (Neurocure Fellowship)

  • Andreas T Grasskamp

Einstein Stiftung Berlin (Einstein Center for Neuroscience)

  • Meida Jusyte
  • Alexander M Walter

University of Copenhagen (Data Science Laboratory)

  • Janus R L Kobbersmed

Lundbeck Foundation (R277-2018-802)

  • Jakob Balslev Sørensen

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

Reviewing Editor

  1. Mark CW van Rossum, University of Nottingham, United Kingdom

Publication history

  1. Received: August 12, 2019
  2. Accepted: February 14, 2020
  3. Accepted Manuscript published: February 20, 2020 (version 1)
  4. Version of Record published: April 9, 2020 (version 2)

Copyright

© 2020, Kobbersmed 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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