Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances
- University of Copenhagen, Denmark
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany
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
Janus R L Kobbersmed
Andreas T Grasskamp
Jakob Balslev Sørensen
Alexander M Walter
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.
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.
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Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances
eLife 9:e51032.
https://doi.org/10.7554/eLife.51032
