Spatiotemporal dynamics of multi-vesicular release is determined by heterogeneity of release sites in central synapses

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Abstract

Synaptic active zone (AZ) can release multiple vesicles in response to an action potential. This multi-vesicular release (MVR) occurs at most synapses, but its spatiotemporal properties are unknown. Nanoscale-resolution detection of individual release events in hippocampal synapses revealed unprecedented heterogeneity among vesicle release sites within a single AZ, with a gradient of release probability decreasing from AZ center to periphery. Parallel to this organization, MVR events preferentially overlap with uni-vesicular release (UVR) events at sites closer to AZ center. Pairs of fusion events comprising MVR are also not perfectly synchronized, and the earlier event tends to occur closer to AZ center. The spatial features of release sites and MVR events are similarly tightened by buffering intracellular calcium. These observations revealed a marked heterogeneity of release site properties within individual AZs, which determines the spatiotemporal features of MVR events and is controlled, in part, by non-uniform calcium elevation across the AZ.

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

Article and author information

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Dario Maschi

Department of Cell Biology and Physiology, Washington University, St Louis, United States

Competing interests
The authors declare that no competing interests exist.
Vitaly Klyachko

Department of Cell Biology and Physiology, Washington University, St Louis, United States

For correspondence
klyachko@wustl.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3449-243X

Funding

National Institute of Neurological Disorders and Stroke (NS111596)

Vitaly Klyachko

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 animal procedures conformed to the guidelines approved by the Washington University Animal Studies Committee (protocol approval # 20170233).

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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.