Abstract
Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through the interaction of VGLUT1 second proline-rich domain, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between Src homology 3 and proline-rich domains of synaptic proteins. In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of SV organization and spontaneous release.
Data availability
Raw measures and intermediate data processing of images and electrophysiology traces are submited in source files appended to this submission.Source images and electrophysiology traces reported in this study are fully available upon request to the corresponding author (Etienne Herzog - https://orcid.org/0000-0002-0058-6959).
Article and author information
Author details
Fabrice P Cordelières
Funding
Agence Nationale de la Recherche (ANR-12-JSV4-0005-01 VGLUT-IQ)
- Etienne Herzog
Agence Nationale de la Recherche (ANR-10-LABX-43 BRAIN)
- Yann Humeau
- Etienne Herzog
Agence Nationale de la Recherche (ANR-10-IDEX-03-02 PEPS SV-PIT)
- Etienne Herzog
Agence Nationale de la Recherche (PSYVGLUT 09-MNPS-033)
- Salah El Mestikawy
Agence Nationale de la Recherche (ANR-10-INBS-04)
- Fabrice P Cordelières
European Commission (Erasmus-Mundus European Neuroscience Campus Program)
- Xiao Min Zhang
- Etienne Herzog
Fondation pour la Recherche Médicale (FDT20120925288)
- Kätlin Silm
Fondation pour la Recherche Médicale (ING20150532192)
- Maria Florencia Angelo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The experimental design and all procedures were in accordance with the European guide for the care and use of laboratory animals, approved by the ethics committee of Bordeaux Universities (CE50), and registered with the french ministry for research under the APAFIS n{degree sign}1692. Every effort was made to minimize the number of animals used and their suffering.
Reviewing Editor
- Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany
Publication history
- Received: July 22, 2019
- Accepted: October 27, 2019
- Accepted Manuscript published: October 30, 2019 (version 1)
- Version of Record published: November 18, 2019 (version 2)
Copyright
© 2019, Zhang 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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