Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release
Open accessPreprint — published as 10.7554/elife.90632
Abstract
Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca 2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca 2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca 2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.
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Approximately 35% of the total release after a single action potential is contributed by asynchronous release in mouse hippocampal excitatory synapses.
“Based on previous studies with zap-and-freeze, patch-clamp electrophysiology measurements, and glutamate imaging, ~35% of the total release that occurs after a single action potential is contributed by this asynchronous component in mouse hippocampal excitatory synapses62,66.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [66]
In excitatory mouse hippocampal neurons, the calcium sensor Doc2α drives the majority of asynchronous release after a single action potential.
“In excitatory mouse hippocampal neurons, the calcium sensor Doc2α drives the majority of asynchronous release after a single action potential66,67.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [66]
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Cites
Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis
Zhou, Q., Lai, Y., Bacaj, T., Zhao, M., Lyubimov, A. Y., Uervirojnangkoorn, M., Zeldin, O. B., Brewster, A. S., Sauter, N. K., Cohen, A. E., et al. (2015) · Nature · doi:10.1038/nature14975 · Cited by 348 · cited 1× · see citing works
“…direct competition between Doc2 α and syt1 could indicate a need to act at a limited number of ‘slots’ at the release site (e.g., SNARE complexes or lipid clusters; Chen et al., 2021 ; Groffen et al., 2010 ; Honigmann et al., 2013 ; Kobbersmed et al., 2022 ; Yao et al., 2011 ; Zhou et al., 2015 ).”
BackgroundSynapsEM: Computer-Assisted Synapse Morphometry
Watanabe, S., Davis, M. W., Kusick, G. F., Iwasa, J., & Jorgensen, E. M. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.584549 · Cited by 34 · see citing works
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Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis
Ogunmowo, T. H., Jing, H., Raychaudhuri, S., Kusick, G. F., Imoto, Y., Li, S., Itoh, K., Ma, Y., Jafri, H., Dalva, M. B., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38595-2 · Cited by 51 · see citing works
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- Authors
- Wu, Z., Kusick, G. F., Berns, M. M. M., Raychaudhuri, S., Itoh, K., Walter, A. M., Chapman, E. R., & Watanabe, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- University of Copenhagen (DK)
- Corresponding author
- Chapman, Edwin R.
- Watanabe, Shigeki
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2022-04-21
- OpenAlex
- W4280555800
- Cited by
- 13
- References
- 2
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 7 · 2022: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, cc-by)
- Funders
- National Science Foundation (2016217537, 1727260)
- Howard Hughes Medical Institute
- McKnight Foundation
- Johns Hopkins University
- National Institutes of Health (1s10rr026445-01, MH061876)
- National Institute of General Medical Sciences (T32GM007445)
- National Institute of Neurological Disorders and Stroke (R35NS097362)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- synaptotagmin 7, asynchronous neurotransmitter release, synaptic vesicle docking, calcium sensor, synaptic facilitation, repetitive stimulation, hippocampal synapses, exocytosis, synaptotagmin-1, synaptic depression
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