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

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

Publication 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.

Metrics

  • 2,858
    Page views
  • 558
    Downloads
  • 35
    Citations

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

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)

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

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

  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
  1. Further reading

Further reading

    1. Neuroscience
    Michael Kintscher, Olexiy Kochubey, Ralf Schneggenburger
    Research Article Updated

    During fear learning, defensive behaviors like freezing need to be finely balanced in the presence or absence of threat-predicting cues (conditioned stimulus, CS). Nevertheless, the circuits underlying such balancing are largely unknown. Here, we investigate the role of the ventral tail striatum (vTS) in auditory-cued fear learning of male mice. In vivo Ca2+ imaging showed that sizable sub-populations of direct (D1R+) and indirect pathway neurons (Adora+) in the vTS responded to footshocks, and to the initiation of movements after freezing; moreover, a sub-population of D1R+ neurons increased its responsiveness to an auditory CS during fear learning. In-vivo optogenetic silencing shows that footshock-driven activity of D1R+ neurons contributes to fear memory formation, whereas Adora+ neurons modulate freezing in the absence of a learned CS. Circuit tracing identified the posterior insular cortex (pInsCx) as an important cortical input to the vTS, and recording of optogenetically evoked EPSCs revealed long-term plasticity with opposite outcomes at the pInsCx synapses onto D1R+ - and Adora+ neurons. Thus, direct- and indirect pathways neurons of the vTS show differential signs of plasticity after fear learning, and balance defensive behaviors in the presence and absence of learned sensory cues.