Synaptic tagging and long-term potentiation
Abstract
Repeated stimulation of hippocampal neurons can induce an immediate and prolonged increase in synaptic strength that is called long-term potentiation (LTP)-the primary cellular model of memory in the mammalian brain. An early phase of LTP (lasting less than three hours) can be dissociated from late-phase LTP by using inhibitors of transcription and translation, Because protein synthesis occurs mainly in the cell body, whereas LTP is input-specific, the question arises of how the synapse specificity of late LTP is achieved without elaborate intracellular protein trafficking. We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.
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BDNF action was selective on the spines that showed immediate enlargement, which may act as the structural tag for selective trapping of the protein-synthetic machinery and the capture of plasticity proteins for long-term spine-head enlargement.
“BDNF action was selective on the spines that showed immediate enlargement, which may act as the structural tag for selective trapping (26) of the protein-synthetic machinery (11, 27) and the capture of plasticity proteins (2, 28) for long-term spine-head enlargement.”
From Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines (2008) · cites this paper as [28]
Stronger stimulation produces dopamine-dependent protein synthesis that allows late LTP.
“stronger stimulation produces the dopamine-dependent protein synthesis that allows late LTP.”
From A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP (2011) · cites this paper as [9]
Weak stimulation induces only early LTP.
“According to this model, weak stimulation induces only early LTP.”
From A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP (2011) · cites this paper as [9]
The synapses that produce PRPs can be different from those at which the tag is set.
“However, the synapses that produce the PRPs can be different from those at which the tag is set.”
From A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP (2011) · cites this paper as [9]
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Hardingham, G. E., Arnold, F. J. L., & Bading, H. (2001) · Nature Neuroscience · doi:10.1038/85109 · Cited by 537 · see citing works
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“The products of de novo protein synthesis are hypothesized to be ‘‘captured’’ at active synapses (Frey and Morris, 1997), but their identity remains unknown.”
BackgroundTranslational Regulatory Mechanisms in Persistent Forms of Synaptic Plasticity
Kelleher, R. J., Govindarajan, A., & Tonegawa, S. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.013 · Cited by 592 · see citing works
“immediate effect (Nguyen et al., 1994; Frey et al., 1996; Frey and Morris, 1997; Scharf et ton et al., 2001). al., 2002).”
BackgroundInfluentialPhenomenological models of synaptic plasticity based on spike timing
Morrison, A., Diesmann, M., & Gerstner, W. (2008) · Biological Cybernetics · doi:10.1007/s00422-008-0233-1 · Cited by 593 · see citing works
Depolarization and cAMP Elevation Rapidly Recruit TrkB to the Plasma Membrane of CNS Neurons
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Mesolimbic dopaminergic pathways in fear conditioning
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Impaired Spatial Learning after Saturation of Long-Term Potentiation
Moser, E. I., Krobert, K. A., Moser, M.-B., & Morris, R. G. M. (1998) · Science · doi:10.1126/science.281.5385.2038 · Cited by 505 · see citing works
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A neuromodulatory role of interleukin-1β in the hippocampus
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“…are synthesized in the cell body and then tarand dictates which mRNAs are polyadenylated (Fox etgeted to the synapse that was “tagged” during the initial al., 1989; McGrew et al., 1989; Huarte et al., 1992; re-stimulation (Sossin, 1996; Frey and Morris, 1997; Schuviewed in Richter, 1996).”
BackgroundMorris, R., Moser, E. I., Riedel, G., Martin, S. J., Sandin, J., Day, M., & O’Carroll, C. (2003) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2002.1264 · Cited by 480 · see citing works
“A new perspective on these ideas is the synaptic tagging hypothesis of memory trace formation (Frey & Morris 1997, 1998a,b; Morris & Frey 1997; Dudai & Morris 2001).”
BackgroundPlant, K., Pelkey, K. A., Bortolotto, Z. A., Morita, D., Terashima, A., McBain, C. J., Collingridge, G. L., & Isaac, J. T. R. (2006) · Nature Neuroscience · doi:10.1038/nn1678 · Cited by 542 · see citing works
In situ visualization and dynamics of newly synthesized proteins in rat hippocampal neurons
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“Thus far, the capture of new proteins has been inferred by clever electrophysiological and pharmacological manipulation”
BackgroundA neoHebbian framework for episodic memory; role of dopamine-dependent late LTP
Lisman, J., Grace, A. A., & Duzel, E. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.07.006 · Cited by 465 · see citing works
Calcium Regulation of Dendritic Growth via CaM Kinase IV and CREB-Mediated Transcription
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New views of Arc, a master regulator of synaptic plasticity
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“From the point of view of hippocampal LTP and LTD, one might therefore conclude that Arc induction is critical for protein synthesis–dependent consolidation of synaptic modifications, regardless of the polarity of the change.”
ResultDevelopment and arealization of the cerebral cortex
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The staufen/pumilio Pathway Is Involved in Drosophila Long-Term Memory
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The role of calmodulin as a signal integrator for synaptic plasticity
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New life in an old idea: The synaptic plasticity and memory hypothesis revisited
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BDNF and Hippocampal Synaptic Plasticity
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“Frey and Morris (1997) have proposed that stimulated synapses produce local “tags” that recruit Discussion newly synthesized macromolecules into dendritic spines.”
BackgroundBiochemical mechanisms for translational regulation in synaptic plasticity
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“This enduring phase has distinct kinetic patterns of sensitivity to transcription and translation inhibitors: the former producing a delayed inhibition, and the latter impeding the initiation of the enduring plasticit”
BackgroundNeuromodulated Spike-Timing-Dependent Plasticity, and Theory of Three-Factor Learning Rules
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“The biological plausibility of eligibility traces and its potential relation to synaptic “tags” (Frey and Morris, 1997; Bailey et al., 2000; Redondo and Morris, 2011) will be explored in the discussion section.”
BackgroundInfluentialNoradrenergic mechanisms in neurodegenerative diseases: a theory
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Translational control of hippocampal synaptic plasticity and memory by the eIF2α kinase GCN2
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Nitric Oxide Signaling Contributes to Late-Phase LTP and CREB Phosphorylation in the Hippocampus
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“…and Apl ysia suggests that local events that occur during early-phase LTP or facilitation somehow " tag " the active synapses, so that those synapses can use the newly synthesized proteins when they arrive from the cell body for the late phase (Frey and Morris, 1997; Martin et al., 1997a).”
BackgroundCommunication Between the Synapse and the Nucleus in Neuronal Development, Plasticity, and Disease
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“Late-LTP also requires protein synthesis: An initial, strong, late-LTP-inducing stimulus at one set of inputs allows the subsequent weak stimulation of a separate synapse—one that, if given on its own, would normally not induce late-LTP—to induce late-LTP at the second synapse (Frey & Morris 1997).”
Background
- Authors
- Frey, U., & Morris, R. G. M.
- Venue
- Nature
- Published
- 1997-02
- Volume
- 385
- Issue
- 6616
- Pages
- 533-536
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2011882079
- Cited by
- 1,736
- References
- 25
- Citations by year
- 2026: 56 · 2025: 48 · 2024: 94 · 2023: 65 · 2022: 75 · 2021: 78 · 2020: 69 · 2019: 68 · 2018: 72 · 2017: 66 · 2016: 72 · 2015: 78 · 2014: 104 · 2013: 56 · 2012: 59
- FWCI
- 17.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- synaptic tagging, long-term potentiation, late-phase LTP, protein synthesis, hippocampal neurons, tetanic stimulation, synaptic specificity, memory, synaptic plasticity
- MeSH terms
- Animals, Anisomycin, Electric Stimulation, Evoked Potentials, Hippocampus, Male, Memory, Models, Neurological, Protein Synthesis Inhibitors, Synapses, Protein Biosynthesis, Rats, Wistar, Long-Term Potentiation, Rats, In Vitro Techniques
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