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Ultrafast endocytosis at mouse hippocampal synapses
Open accessAbstract
To sustain neurotransmission, synaptic vesicles and their associated proteins must be recycled locally at synapses. Synaptic vesicles are thought to be regenerated approximately 20 s after fusion by the assembly of clathrin scaffolds or in approximately 1 s by the reversal of fusion pores via 'kiss-and-run' endocytosis. Here we use optogenetics to stimulate cultured hippocampal neurons with a single stimulus, rapidly freeze them after fixed intervals and examine the ultrastructure using electron microscopy--'flash-and-freeze' electron microscopy. Docked vesicles fuse and collapse into the membrane within 30 ms of the stimulus. Compensatory endocytosis occurs within 50 to 100 ms at sites flanking the active zone. Invagination is blocked by inhibition of actin polymerization, and scission is blocked by inhibiting dynamin. Because intact synaptic vesicles are not recovered, this form of recycling is not compatible with kiss-and-run endocytosis; moreover, it is 200-fold faster than clathrin-mediated endocytosis. It is likely that 'ultrafast endocytosis' is specialized to restore the surface area of the membrane rapidly.
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“Several recent studies suggest that synaptic vesicle endocytosis is mediated by clathrin-independent ultrafast endocytosis at mammalian central synapses and is tightly coupled to exocytosis in time and space5–9.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Thus, the actin ring surrounding the active zone is likely essential for ultrafast endocytosis5.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“Indeed, ultrafast endocytosis initiates as fast as 20–50 ms after exocytosis and completes within 100 ms5–7.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“In this pathway, endocytic invaginations always form at the edge of the active zone5–7.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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In the citing paper
“Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [32]
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“Ultrafast endocytosis occurs rapidly, within 50–100 milliseconds following stimulation, capturing approximately four vesicles at the very edge of the active zone [32]. This mechanism is specialized for rapidly restoring the surface area of the presynaptic membrane and is kinetically distinct from both kiss-and-run and clathrin-mediated endocytosis [33].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [32]
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In the citing paper
“Several recent studies suggest that synaptic vesicle endocytosis is mediated by clathrin-independent ultrafast endocytosis at mammalian central synapses and is tightly coupled to exocytosis in time and space5–9.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“Consistent with our previous work5, treatment with DMSO (control) did not affect ultrafast endocytosis, while Latrunculin A treatment completely blocked it (Fig. 2c, d; more micrographs in Supplementary Fig. 4).”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“Importantly, the timing and the location of endocytic pit formation quantitatively recapitulates endocytic events observed by ultrastructural analysis5,6.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“Filamentous actin (F-actin) is essential for the initiation of ultrafast endocytosis5.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“When neurons are treated with Latrunculin A, which sequesters monomeric actin (G-actin) and perturbs F-actin formation12,13, ultrafast endocytosis fails completely, with no induction of membrane pit formation5.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“Interestingly, ultrafast endocytosis is compensatory - the membrane area of endocytic vesicles is roughly equal to the total surface area of synaptic vesicles exocytosed5,6”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [5]
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“Kiss-and-run is a rapid mechanism that involves a transient opening of a fusion pore, allowing for neurotransmitter release without full collapse of the SV into the plasma membrane [30]. The vesicle is then rapidly retrieved, often within approximately one second [31,32].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [32]
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“Key proteins involved include clathrin itself and dynamin, which mediates the scission of the budding vesicle from the plasma membrane [32].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [32]
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Metadata
- Authors
- Watanabe, S., Rost, B. R., Camacho-Pérez, M., Davis, M. W., Söhl-Kielczynski, B., Rosenmund, C., & Jorgensen, E. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Rosenmund, Christian
- Venue
- Nature
- Published
- 2013-12-04
- Volume
- 504
- Issue
- 7479
- Pages
- 242-247
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3957339
- OpenAlex
- W2093450191
- Cited by
- 607
- References
- 54
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 44 · 2023: 47 · 2022: 53 · 2021: 44 · 2020: 53 · 2019: 62 · 2018: 51 · 2017: 54 · 2016: 36 · 2015: 58 · 2014: 38 · 2013: 1
- FWCI
- 25.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke (R37NS034307, NS034307, R01NS034307)
- 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
- synaptic vesicle recycling, clathrin-mediated endocytosis, dynamin, actin polymerization, hippocampal synapses, neurotransmission, membrane internalization, active zone, optogenetic stimulation
- MeSH terms
- Actins, Action Potentials, Animals, Endocytosis, Exocytosis, Hippocampus, Membrane Fusion, Microscopy, Electron, Synaptic Transmission, Rhodopsin, Synapses, Synaptic Vesicles, Time Factors, Dynamins, Mice
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