Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies Contribute to the Diversity of Synaptic Function
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Abstract
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 Ca 2+ imaging, Ca 2+ 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.
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The corresponding active zone membrane association can be detected by freeze-fracture replica labeling.
“The corresponding AZ membrane association can be detected by FRL [23,61,66,67].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [66]
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Synaptic Vesicle Recycling at the Developing Presynapse
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Charting the nanotopography of inner hair cell synapses using MINFLUX nanoscopy
Kapoor, R., Kim, H., Garlick, E., Lima, M. A. D. R. B. F., Esch, K., Ruhwedel, T., Möbius, W., Wolf, F., & Moser, T. (2025) · Science Advances · doi:10.1126/sciadv.ady4344 · Cited by 2 · see citing works
Satake, S., & Konishi, S. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15487 · Cited by 2 · see citing works
A new method for isolation and purification of fusion-competent inhibitory synaptic vesicles
Gopal, N., Leitz, J., Wang, C., Esquivies, L. R., Pfuetzner, R. A., & Brünger, A. T. (2024) · Current Research in Physiology · doi:10.1016/j.crphys.2024.100121 · Cited by 2 · see citing works
Liu, C., & Kaeser, P. S. (2019) · Neuron · doi:10.1016/j.neuron.2019.10.015 · Cited by 2 · see citing works
- Authors
- Rebola, N., Reva, M., Kirizs, T., Szoboszlay, M., Lőrincz, A., Moneron, G., Nusser, Z., & DiGregorio, D. A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- HUN-REN Institute of Experimental Medicine (HU)
- Corresponding author
- DiGregorio, David A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 104
- Issue
- 4
- Pages
- 693-710.e9
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2977087614
- Cited by
- 136
- References
- 103
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 27 · 2023: 16 · 2022: 19 · 2021: 22 · 2020: 19 · 2019: 3
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-10-06)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- European Research Council (ERC-AG 787157)
- National Research, Development and Innovation Office (14-1-2015-0155)
- Agence Nationale de la Recherche (ANR-17-CE16-0026, ANR-13-BSV4-0016, ANR-17-CE16-0019, ANR-2010-BLANC-1411)
- Centre National de la Recherche Scientifique
- Fondation pour la Recherche Médicale
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- voltage-gated calcium channels, synaptic vesicles, synaptic efficacy, synaptic plasticity, Munc13-1, active zone, vesicle docking, reaction-diffusion modeling, neuromodulation, cerebellar synapses, immunogold electron microscopy
- MeSH terms
- Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Synaptic Transmission, Synapses, Synaptic Vesicles, Calcium Channels, Mice
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