Ultrastructural Correlates of Presynaptic Functional Heterogeneity in Hippocampal Synapses

Although similar in molecular composition, synapses can exhibit strikingly distinct functional transmitter release and plasticity characteristics. To determine whether ultrastructural differences co-define this functional heterogeneity, we combine hippocampal organotypic slice cultures, high-pressure freezing, freeze substitution, and 3D-electron tomography to compare two functionally distinct synapses: hippocampal Schaffer collateral and mossy fiber synapses. We find that mossy fiber synapses, which exhibit a lower release probability and stronger short-term facilitation than Schaffer collateral synapses, harbor lower numbers of docked synaptic vesicles at active zones and a second pool of possibly tethered vesicles in their vicinity. Our data indicate that differences in the ratio of docked versus tethered vesicles at active zones contribute to distinct functional characteristics of synapses. [Display omitted] •Electron tomography enables the dissection of vesicle pools at synaptic active zones•Docked and primed vesicle availability contributes to initial release probability•The ratio of docked and tethered vesicles may co-determine short-term plasticity•Hippocampal mossy fibers contain three morphological types of docked vesicles Distinct synapse types exhibit strikingly different morphological and functional properties. To investigate how the ultrastructural architecture of synaptic release sites contributes to such diversity, Maus et al. exploit electron tomography to correlate the nanoscale organization of synaptic vesicle pools with fundamental functional properties such as short-term synaptic plasticity characteristics.