1. Neuroscience

Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate

  1. Sebastiaan Schotten
  2. Marieke Meijer
  3. Alexander Matthias Walter
  4. Vincent Huson
  5. Lauren Mamer
  6. Lawrence Kalogreades
  7. Mirelle ter Veer
  8. Marvin Ruiter
  9. Nils Brose
  10. Christian Rosenmund
  11. Jakob B. Sørensen
  12. Matthijs Verhage
  13. Lennart Niels Cornelisse  Is a corresponding author
  1. VU University Medical Center, Netherlands
  2. Charité, Universitätsmedizin Berlin, Germany
  3. Max Planck Institute for Experimental Medicine, Germany
  4. University of Copenhagen, Denmark
https://doi.org/10.7554/eLife.05531
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  1. Sebastiaan Schotten
  2. Marieke Meijer
  3. Alexander Matthias Walter
  4. Vincent Huson
  5. Lauren Mamer
  6. Lawrence Kalogreades
  7. Mirelle ter Veer
  8. Marvin Ruiter
  9. Nils Brose
  10. Christian Rosenmund
  11. Jakob B. Sørensen
  12. Matthijs Verhage
  13. Lennart Niels Cornelisse
(2015)
Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate
eLife 4:e05531.
https://doi.org/10.7554/eLife.05531
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  3. Download .RIS

Abstract

The energy required to fuse synaptic vesicles with the plasma membrane ('activation energy') is considered a major determinant in synaptic efficacy. From reaction rate theory we predict that a class of modulations exists, which utilize linear modulation of the energy barrier for fusion to achieve supralinear effects on the fusion rate. To test this prediction experimentally, we developed a method to assess the number of releasable vesicles, rate constants for vesicle priming, unpriming, and fusion, and the activation energy for fusion by fitting a vesicle state model to synaptic responses induced by hypertonic solutions. We show that ComplexinI/II deficiency or phorbol ester stimulation indeed affects responses to hypertonic solution in a supralinear manner. An additive versus multiplicative relationship between activation energy and fusion rate provides a novel explanation for previously observed non-linear effects of genetic/pharmacological perturbations on synaptic transmission and a novel interpretation of the cooperative nature of Ca2+-dependent release.

Article and author information

Author details

  1. Sebastiaan Schotten

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  2. Marieke Meijer

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  3. Alexander Matthias Walter

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  4. Vincent Huson

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  5. Lauren Mamer

    NeuroCure Cluster of Excellence, Charité, Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.

  6. Lawrence Kalogreades

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  7. Mirelle ter Veer

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  8. Marvin Ruiter

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  9. Nils Brose

    Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.

  10. Christian Rosenmund

    NeuroCure Cluster of Excellence, Neuroscience Research Center, Charité, Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    Christian Rosenmund, Reviewing editor, eLife.

  11. Jakob B. Sørensen

    Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.

  12. Matthijs Verhage

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  13. Lennart Niels Cornelisse

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    For correspondence
    l.n.cornelisse@vu.nl
    Competing interests
    No competing interests declared.

Reviewing Editor

  1. Michael Häusser, University College London, United Kingdom

Version history

  1. Received: November 7, 2014
  2. Accepted: April 13, 2015
  3. Accepted Manuscript published: April 14, 2015 (version 1)
  4. Version of Record published: May 12, 2015 (version 2)

Copyright

© 2015, Schotten 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. Sebastiaan Schotten
  2. Marieke Meijer
  3. Alexander Matthias Walter
  4. Vincent Huson
  5. Lauren Mamer
  6. Lawrence Kalogreades
  7. Mirelle ter Veer
  8. Marvin Ruiter
  9. Nils Brose
  10. Christian Rosenmund
  11. Jakob B. Sørensen
  12. Matthijs Verhage
  13. Lennart Niels Cornelisse
(2015)
Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate
eLife 4:e05531.
https://doi.org/10.7554/eLife.05531

Share this article

https://doi.org/10.7554/eLife.05531

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    Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1

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    Previously, we showed that modulation of the energy barrier for synaptic vesicle fusion boosts release rates supralinearly (Schotten, 2015). Here we show that mouse hippocampal synapses employ this principle to trigger Ca2+-dependent vesicle release and post-tetanic potentiation (PTP). We assess energy barrier changes by fitting release kinetics in response to hypertonic sucrose. Mimicking activation of the C2A domain of the Ca2+-sensor Synaptotagmin-1 (Syt1), by adding a positive charge (Syt1D232N) or increasing its hydrophobicity (Syt14W), lowers the energy barrier. Removing Syt1 or impairing its release inhibitory function (Syt19Pro) increases spontaneous release without affecting the fusion barrier. Both phorbol esters and tetanic stimulation potentiate synaptic strength, and lower the energy barrier equally well in the presence and absence of Syt1. We propose a model where tetanic stimulation activates Syt1-independent mechanisms that lower the energy barrier and act additively with Syt1-dependent mechanisms to produce PTP by exerting multiplicative effects on release rates.

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