1. Neuroscience
Download icon

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 8
  • Views 2,472
  • Annotations
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.

Metrics

  • 2,472
    Page views
  • 506
    Downloads
  • 8
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Neuroscience
    Wucheng Tao et al.
    Research Article Updated

    Long-term potentiation (LTP) is arguably the most compelling cellular model for learning and memory. While the mechanisms underlying the induction of LTP (‘learning’) are well understood, the maintenance of LTP (‘memory’) has remained contentious over the last 20 years. Here, we find that Ca2+-calmodulin-dependent kinase II (CaMKII) contributes to synaptic transmission and is required LTP maintenance. Acute inhibition of CaMKII erases LTP and transient inhibition of CaMKII enhances subsequent LTP. These findings strongly support the role of CaMKII as a molecular storage device.

    1. Medicine
    2. Neuroscience
    Zifei Liang et al.
    Tools and Resources

    1H MRI maps brain structure and function non-invasively through versatile contrasts that exploit inhomogeneity in tissue micro-environments. Inferring histopathological information from MRI findings, however, remains challenging due to absence of direct links between MRI signals and cellular structures. Here, we show that deep convolutional neural networks, developed using co-registered multi-contrast MRI and histological data of the mouse brain, can estimate histological staining intensity directly from MRI signals at each voxel. The results provide three-dimensional maps of axons and myelin with tissue contrasts that closely mimics target histology and enhanced sensitivity and specificity compared to conventional MRI markers. Furthermore, the relative contribution of each MRI contrast within the networks can be used to optimize multi-contrast MRI acquisition. We anticipate our method to be a starting point for translation of MRI results into easy-to-understand virtual histology for neurobiologists and provide resources for validating novel MRI techniques.