1. Neuroscience

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

  1. Vincent Huson
  2. Marieke Meijer
  3. Rien Dekker
  4. Mirelle ter Veer
  5. Marvin Ruiter
  6. Jan R T van Weering
  7. Matthijs Verhage
  8. Lennart Niels Cornelisse  Is a corresponding author
  1. Amsterdam University Medical Center- Location VUmc, Netherlands
  2. VU University Medical Center, Netherlands
https://doi.org/10.7554/eLife.55713
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  1. Vincent Huson
  2. Marieke Meijer
  3. Rien Dekker
  4. Mirelle ter Veer
  5. Marvin Ruiter
  6. Jan R T van Weering
  7. Matthijs Verhage
  8. Lennart Niels Cornelisse
(2020)
Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1
eLife 9:e55713.
https://doi.org/10.7554/eLife.55713
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Abstract

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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All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Vincent Huson

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam University Medical Center- Location VUmc, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3556-1436

  2. Marieke Meijer

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam University Medical Center- Location VUmc, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  3. Rien Dekker

    Department of Functional Genomics, Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam University Medical Center- Location VUmc, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6284-3279

  4. Mirelle ter Veer

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  5. Marvin Ruiter

    Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  6. Jan R T van Weering

    Department of Clinical Genetics, Amsterdam University Medical Center- Location VUmc, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  7. Matthijs Verhage

    Department of Clinical Genetics, Amsterdam University Medical Center- Location VUmc, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

  8. Lennart Niels Cornelisse

    Department of Functional Genomics, Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam University Medical Center- Location VUmc, Amsterdam, Netherlands
    For correspondence
    l.n.cornelisse@vu.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9425-2935

Funding

H2020 European Research Council (ERC Advanced Grant,322966)

  • Matthijs Verhage

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (CLS2007,635100020)

  • Lennart Niels Cornelisse

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

Ethics

Animal experimentation: Animals were housed and bred according to institutional and Dutch governmental guidelines, and all procedures are approved by the ethical committee of the Vrije Universiteit, Amsterdam, The Netherlands (Dierexperimentencomissie (DEC) license number: FGA11-03).

Copyright

© 2020, Huson 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. Vincent Huson
  2. Marieke Meijer
  3. Rien Dekker
  4. Mirelle ter Veer
  5. Marvin Ruiter
  6. Jan R T van Weering
  7. Matthijs Verhage
  8. Lennart Niels Cornelisse
(2020)
Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1
eLife 9:e55713.
https://doi.org/10.7554/eLife.55713

Share this article

https://doi.org/10.7554/eLife.55713

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Further reading

    1. Neuroscience

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

    Sebastiaan Schotten, Marieke Meijer ... Lennart Niels Cornelisse
    Research Article Updated

    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 vs 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.