Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies Contribute to the Diversity of Synaptic Function

• Published in: Neuron (Cambridge, Mass.) Mass.), 2019-11, Vol.104 (4), p.693-710.e9
• Main Authors: Rebola, Nelson, Reva, Maria, Kirizs, Tekla, Szoboszlay, Miklos, Lőrincz, Andrea, Moneron, Gael, Nusser, Zoltan, DiGregorio, David A.
• Format: Article
• Language: English
• Subjects: active zone; Animals; Calcium channels; Calcium channels (voltage-gated); Calcium Channels - metabolism; Calcium imaging; calcium-release coupling; Cerebellar plasticity; Cerebellum; Diffusion models; electron microscopy; Laboratories; Life Sciences; Localization; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microscopy; molecular nanotopography; Monte Carlo simulation; multi-photon imaging; Neuromodulation; Neurons and Cognition; Neurosciences; release probability; Signal transduction; Spatial distribution; Structure-function relationships; synapse diversity; Synapses; Synapses - metabolism; Synaptic plasticity; Synaptic strength; Synaptic Transmission - physiology; Synaptic vesicles; Synaptic Vesicles - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.08.014

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. •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 Rebola et al. identified two distinct nanoscale topographies of calcium channels and synaptic vesicles that underlie functional differences in synaptic strength and neuromodulation in cerebellum. These motifs provide new insight into the macromolecular organization mediating synaptic transmission.