Abstract
A 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 an 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.
Highlights
Information transmission in the brain relies critically on the number of vesicles released with each action potential, and major efforts have been made to model this process (Neher, 2010; Pan and Zucker, 2009; Rotman et al, 2011)
multi-vesicular release (MVR) preferentially occurs at release sites with higher release probability and is more likely to overlap with uni-vesicular release (UVR) closer to the active zone (AZ) center
(iii) The gradient of release site properties as well as spatiotemporal features of MVR, are determined, in part, by the intraterminal calcium elevation following an action potential. Together these results suggest that non-uniform spatiotemporal dynamics of MVR arises from heterogeneity of release site properties within the individual AZs
Summary
Information transmission in the brain relies critically on the number of vesicles released with each action potential, and major efforts have been made to model this process (Neher, 2010; Pan and Zucker, 2009; Rotman et al, 2011). Spatiotemporal organization of MVR within the synaptic active zone (AZ) and its regulation are poorly understood. Investigating these questions has been hampered by the extremely small size of the AZ (Schikorski and Stevens, 1997, 1999), and limited resolution of conventional experimental approaches. As a result, it remains unknown whether all release sites within the AZ support both UVR and MVR, or specialized subsets of release sites are preferentially used for one form or the other. A fundamental unresolved question is whether all release sites are uniform in their properties across the AZ, or a more complex spatiotemporal landscape of release features exists within individual AZs and controls the occurrence of UVR and MVR
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