The readily-releasable pool dynamically regulates multivesicular release

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Abstract

The number of neurotransmitter-filled vesicles released into the synaptic cleft with each action potential dictates the reliability of synaptic transmission. Variability of this fundamental property provides diversity of synaptic function across brain regions, but the source of this variability is unclear. The prevailing view is that release of a single (univesicular release, UVR) or multiple vesicles (multivesicular release, MVR) reflects variability in vesicle release probability, a notion that is well-supported by the calcium-dependence of release mode. However, using mouse brain slices, we now demonstrate that the number of vesicles released is regulated by the size of the readily-releasable pool, upstream of vesicle release probability. Our results point to a model wherein protein kinase A and its vesicle-associated target, synapsin, dynamically controls release site occupancy to dictate the number of vesicles released without altering release probability. Together these findings define molecular mechanisms that control MVR and functional diversity of synaptic signaling.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Mathematica files for the FD2 model have been deposited in ModelDB (senselab.med.yale.edu/modeldb/).

The following data sets were generated

(2019) Vesicle release model
senselab.med.yale.edu/modeldb/.

https://senselab.med.yale.edu/

Article and author information

Author details

Jada H Vaden

Department of Neurobiology, University of Alabama at Birmingham, Birmingham, United States

Competing interests
The authors declare that no competing interests exist.
Gokulakrishna Banumurthy

Department of Neurobiology, University of Alabama at Birmingham, Birmingham, United States

Competing interests
The authors declare that no competing interests exist.
Eugeny S Gusarevich

Department of Fundamental and Applied Physics, Northern (Arctic) Federal University named after M V Lomonosov, Arkhangelsk, Russian Federation

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8642-6293
Linda Overstreet-Wadiche

Department of Neurobiology, University of Alabama at Birmingham, Birmingham, United States

For correspondence
lwadiche@uab.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7367-5998
Jacques I Wadiche

Department of Neurobiology, University of Alabama at Birmingham, Birmingham, United States

For correspondence
jwadiche@uab.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8180-2061

Funding

National Institute of Neurological Disorders and Stroke (NS065920)

Jacques I Wadiche

National Institute of Neurological Disorders and Stroke (NS064025)

Linda Overstreet-Wadiche

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

Ethics

Animal experimentation: All experiments were conducted through protocols approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham under protocol #08767.

Copyright

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.