Neuron
Volume 104, Issue 4, 20 November 2019, Pages 693-710.e9
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Article
Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies Contribute to the Diversity of Synaptic Function

https://doi.org/10.1016/j.neuron.2019.08.014Get rights and content
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Highlights

  • Number of presynaptic calcium channels (CaV) does not correlate with synaptic strength

  • Weak synapses are more sensitive to competition with exogenous Ca2+ chelators

  • EM immunogold labeling of CaV2.1 and Munc13-1 shows synapse-specific nanotopographies

  • Different nanoscale CaV-synaptic vesicle arrangements explain functional differences

Summary

The nanoscale topographical arrangement of voltage-gated calcium channels (VGCC) and synaptic vesicles (SVs) determines synaptic strength and plasticity, but whether distinct spatial distributions underpin diversity of synaptic function is unknown. We performed single bouton Ca2+ imaging, Ca2+ chelator competition, immunogold electron microscopic (EM) localization of VGCCs and the active zone (AZ) protein Munc13-1, at two cerebellar synapses. Unexpectedly, we found that weak synapses exhibited 3-fold more VGCCs than strong synapses, while the coupling distance was 5-fold longer. Reaction-diffusion modeling could explain both functional and structural data with two strikingly different nanotopographical motifs: strong synapses are composed of SVs that are tightly coupled (∼10 nm) to VGCC clusters, whereas at weak synapses VGCCs were excluded from the vicinity (∼50 nm) of docked vesicles. The distinct VGCC-SV topographical motifs also confer differential sensitivity to neuromodulation. Thus, VGCC-SV arrangements are not canonical, and their diversity could underlie functional heterogeneity across CNS synapses.

Keywords

synapse diversity
release probability
active zone
molecular nanotopography
calcium-release coupling
multi-photon imaging
electron microscopy
Monte Carlo simulation
neuromodulation

Cited by (0)

3

Present address: Mortimer B. Zuckerman Mind Brain Behavior Institute, Department of Neuroscience, Columbia University, New York, NY, USA

4

Present address: ICM, Brain and Spine Institute, Hopital de la Pitie-Salpetriere, Sorbonne Universite, Inserm, CNRS, Paris 75013, France

5

These authors contributed equally

6

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