Real-Time Imaging of Discrete Exocytic Events Mediating Surface Delivery of AMPA Receptors
Open accessAbstract
We directly resolved discrete exocytic fusion events mediating insertion of AMPA-type glutamate receptors (AMPARs) to the somatodendritic surface of rat hippocampal pyramidal neurons, in slice and dissociated cultures, using protein tagging with a pH-sensitive GFP (green fluorescent protein) variant and rapid (10 frames/s) fluorescence microscopy. AMPAR-containing exocytic events occurred under basal culture conditions in both the cell body and dendrites; potentiating chemical stimuli produced an NMDA receptor-dependent increase in the frequency of individual exocytic events. The number of AMPARs inserted per exocytic event, estimated using single-molecule analysis, was quite uniform but individual events differed significantly in kinetic properties affecting the subsequent surface distribution of receptors. “Transient” events, from which AMPARs dispersed laterally immediately after surface insertion, generated a pronounced but short-lived (dissipating within ∼1 s) increase in surface AMPAR fluorescence extending locally (2–5 μm) from the site of exocytosis. “Persistent” events, from which inserted AMPARs dispersed slowly (typically over 5–10 s), affected local surface receptor concentration to a much smaller degree. Both modes of exocytic insertion occurred throughout the dendritic shaft, but remarkably, neither mode of insertion was observed directly into synaptic spines. AMPARs entered spines preferentially from transient events occurring in the adjoining dendritic shaft, driven apparently by mass action and short-range lateral diffusion, and locally delivered AMPARs remained mostly in the mobile fraction. These results suggest a highly dynamic mechanism for both constitutive and activity-dependent surface delivery of AMPARs, mediated by kinetically distinct exocytic modes that differ in propensity to drive lateral entry of receptors to nearby synapses.
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Blocking postsynaptic exocytosis by a variety of means blocks LTP/sLTP.
“Numerous studies have shown that blocking postsynaptic exocytosis by a variety of means blocks LTP/sLTP (195, 249, 250, 332–338).”
From Synaptic memory and CaMKII (2023) · cites this paper as [337]
The Results section ('Resolving distinct exocytic insertion modes'; page not available) reports that potentiating stimuli increase AMPA-receptor exocytic events, and the Discussion says receptor delivery plays a critical role in initiating synaptic potentiation. The paper does not report that blocking postsynaptic exocytosis—by any means—blocks LTP or sLTP. (LLM, conf=0.82)
Experimental — accuracy not yet measuredBy tagging AMPARs with a pH-sensitive tag (SEP-GluA1), insertion of AMPARs into the surface membrane can be directly visualized during LTP-inducing protocols.
“By tagging AMPARs with a pH-sensitive tag (SEP-GluA1), the insertion of AMPARs into the surface membrane can be directly visualized during LTP-inducing protocols (249, 250, 335, 337, 338, 340).”
From Synaptic memory and CaMKII (2023) · cites this paper as [337]
In most cases AMPARs are inserted via exocytosis into the dendritic shaft, some distance from the synapse.
“Fourth, in most cases the AMPARs are inserted via exocytosis into the dendritic shaft, some distance from the synapse (220, 249, 250, 337).”
From Synaptic memory and CaMKII (2023) · cites this paper as [337]
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Cites
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“4E,F) suggests a simple “averaging” principle to reduce the stochastic noise in surface AMPAR insertion inherent to the regulation of individual exocytic events (Franks et al., 2003), potentially enhancing the reliability and precision of surface AMPAR delivery to individual synapses.”
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- Authors
- Yudowski, G. A., Puthenveedu, M. A., Leonoudakis, D., Panicker, S., Thorn, K. S., Beattie, E. C., & von Zastrow, M.
- Affiliations
- University of California, San Francisco (US)
- California Pacific Medical Center (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-10-10
- Volume
- 27
- Issue
- 41
- Pages
- 11112-11121
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3249441
- OpenAlex
- W2047850618
- Cited by
- 197
- References
- 8
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 10 · 2014: 10 · 2013: 18 · 2012: 17
- FWCI
- 7.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- KiltHub Repository
- Funders
- National Institutes of Health (DA010711)
- University of California, San Francisco (DA010711)
- National Institute of Mental Health (MH067931, R01MH067931)
- National Institute on Drug Abuse (DA010711, R29DA010711, R37DA010711, K99DA023444, R01DA010711)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- AMPA receptors, exocytosis, hippocampal pyramidal neurons, dendritic spines, NMDA receptor, lateral diffusion, single-molecule analysis, synaptic plasticity
- MeSH terms
- Animals, Animals, Newborn, Cell Membrane, Computer Systems, Exocytosis, Hippocampus, Organ Culture Techniques, Receptors, Cell Surface, Receptors, AMPA, Excitatory Postsynaptic Potentials, Rats
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