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Synaptic tagging and long-term potentiation

Frey, Uwe, Morris, Richard G. M.·1997·Nature

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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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Background
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Morris, R. (2002) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780198508809.003.0011 · Cited by 17
Making memories last using the peripheral effect of direct current stimulation
Luckey, A. M., McLeod, S. L., Huang, Y., Mohan, A., & Vanneste, S. (2023) · eLife · doi:10.7554/elife.75586 · Cited by 16
“…model known as the synaptic tag- and- capture hypothesis that has proposed a cellular mechanism explaining how new memories that are initially weak and unstable are tagged to be captured by late- phase long- term potentiation (LTP) to become stable (Morris and Frey, 1997; Frey and Morris, 1997).”
Infant Cognitive Training Preshapes Learning-Relevant Prefrontal Circuits for Adult Learning: Learning-Induced Tagging of Dendritic Spines
Bock, J., Poeggel, G., Gruss, M., Wingenfeld, K., & Braun, K. A. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht148 · Cited by 17
Long-Term Potentiation: Mechanisms of Induction and Maintenance
Blitzer, R. D. (2005) · Science s STKE · doi:10.1126/stke.3092005tr26 · Cited by 19
“The maintenance of LTP beyond 1 to 3 hours in the slice requires de novo protein synthesis, as shown by the transient potentiation obtained when HFS is delivered in the presence of translation or transcription inhibitors [for example, see (17, 18)].”
Background
A new mechanism of synapse-specific neuronal plasticity
Nikitin, V. P. (2007) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-007-0053-0 · Cited by 17
“A molecular genetic program for the formation of long-term synapse-specific plasticity similar to that observed in Aplysia neurons evidently occurs in mammalian hippocampal neurons on acquisition of long-term potentiation (LTP) [40].”
BackgroundInfluential
Tagging the Hebb synapse
Routtenberg, A. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01412-5 · Cited by 17
Enhancement of Glutamate Release by l-Fucose Changes Effects of Glutamate Receptor Antagonists on Long-Term Potentiation in the Rat HippocampusPreprint
Matthies, H., Schröeder, H., Smalla, K., & Krug, M. (2000) · Learning & Memory · doi:10.1101/lm.7.4.227 · Cited by 17
“This synaptic enhancement, lasting hours or days, is discussed as a possible cellular mechanism involved in learning and memory formation (Bliss and Collingridge 1993; Frey and Morris 1997 ).”
In memoriam: John Lisman – commentaries on CaMKII as a memory molecule
Bear, M. F., Cooke, S. F., Giese, K.-P., Kaang, B., Kennedy, M. B., Kim, J., Morris, R., & Park, P. (2018) · Molecular Brain · doi:10.1186/s13041-018-0419-y · Cited by 17
Brain-wide measurement of synaptic protein turnover reveals localized plasticity during learningPreprint
Mohar, B., Michel, G., Wang, Y., Hernandez, V., Grimm, J. B., Park, J.-Y., Patel, R. H., Clarke, M., Brown, T. A., Bergmann, C., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.12.516226 · Cited by 17
Modern Artificial Neural Networks: Is Evolution Cleverer?
Bahmer, A., Gupta, D. S., & Effenberger, F. (2023) · Neural Computation · doi:10.1162/neco_a_01575 · Cited by 17
“This is called “synaptic tagging” (Redondo & Morris, 2011; Frey & Morris, 1997).”
Synapses tagged, memories kept: synaptic tagging and capture hypothesis in brain health and disease
Ibrahim, M. Z. B., Wang, Z., & Sajikumar, S. (2024) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2023.0237 · Cited by 16
“Timeline depicting key studies in understanding fundamental properties of STC [2,3] and how STC has been used in different ways to inform on synaptic plasticity processes.”
BackgroundMethodInfluential
Modulating the map
Werlen, E., & Jones, M. W. (2015) · Progress in brain research · doi:10.1016/bs.pbr.2015.03.002 · Cited by 16
The various forms of neuroplasticity: Biological bases of learning and teaching
Tovar-Moll, F. F., & Lent, R. (2016) · Prospects · doi:10.1007/s11125-017-9388-7 · Cited by 21
“From the nucleus, then, newly formed mRNAs and proteins are carried back to the originally activated synapses, which are thought to have been ‘‘tagged’’ by the previous synaptically-transmitted information (Frey and Morris 1997).”
Background
Impact of Structural Plasticity on Memory Formation and Decline
Knoblauch, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803784-3.00017-2 · Cited by 17
Brief periods of NREM sleep do not promote early offline gains but subsequent on-task performance in motor skill learning
Maier, J. G., Piosczyk, H., Holz, J., Landmann, N., Deschler, C., Frase, L., Kühn, M., Klöppel, S., Spiegelhalder, K., Sterr, A., et al. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.08.006 · Cited by 17
“Sleep-specific activity on task-related synapses ‘tagged’ during training (Frey & Morris, 1997; Redondo et al., 2010) or processes of neural replay of task-specific activity during sleep (Ramanathan, Gulati, & Ganguly, 2015; Ribeiro & Nicolelis, 2004) might contribute to a preferential…”
Background
Novelty exposure modulates visual and verbal emotional memory: An experimental design with adults
Abrahan, V. D., Psyrdellis, M., & Justel, N. R. (2020) · Acta Psychologica · doi:10.1016/j.actpsy.2020.103029 · Cited by 17
Memory Evolutive Systems
Mary, R. (2007) · Studies in multidisciplinarity · doi:10.1016/s1571-0831(06)04001-9 · Cited by 17
Short-term plasticity as cause–effect hypothesis testing in distal reward learning
Soltoggio, A. (2014) · Biological Cybernetics · doi:10.1007/s00422-014-0628-0 · Cited by 27
Postinduction Requirement of NMDA Receptor Activation for Late-Phase Long-Term Potentiation of Developing Retinotectal SynapsesIn Vivo
Gong, L.-Q., He, L.-J., Dong, Z.-Y., Lu, X.-H., Poo, M., & Zhang, X.-H. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5936-10.2011 · Cited by 16
“The effective interval of spaced neural activities for inducing protein synthesis-dependent L-LTP varied from seconds to minutes in different systems (Nguyen et al., 1994; Huang et al., 1996; Mauelshagen et al., 1996; Frey and Morris, 1997; Kandel, 2001).”
Background
Intermittent fasting promotes prolonged associative interactions during synaptic tagging/capture by altering the metaplastic properties of the CA1 hippocampal neurons
Dasgupta, A., Kim, J., Manakkadan, A., Arumugam, T. V., & Sajikumar, S. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.12.004 · Cited by 16
“STC describes an additional associative property of activity dependent synaptic plasticity, by emphasizing the time-dependent associative interaction of sequentially activated synaptic inputs (Frey and Morris, 1997; Shivarama Shetty and Sajikumar, 2017).”
Embodied Synaptic Plasticity With Online Reinforcement Learning
Kaiser, J., Hoff, M., Konle, A., Tieck, J. C. V., Kappel, D., Reichard, D., Subramoney, A., Legenstein, R. A., Roennau, A., Maass, W., et al. (2019) · Frontiers in Neurorobotics · doi:10.3389/fnbot.2019.00081 · Cited by 14
“This concept has been observed in the brain (Frey and Morris, 1997; Pan et al., 2005), and SPORE also relies on eligibility traces.”
Background
Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons
Squires, K. E., Gerber, K. J., Tillman, M. C., Lustberg, D. J., Montañez‐Miranda, C., Zhao, M., Ramineni, S., Scharer, C. D., Saha, R. N., Shu, F., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.016009 · Cited by 15
“Signals from the activated synapse must reach the nucleus, and newly synthesized mRNA must reach the activated synapse within a relatively short window in order to support synaptic strengthening and maturation (58).”
Background
The Behavioral Tagging Hypothesis and Its Implications for Long-Term Memory Formation
Moncada, D., Ballarini, F., Martínez, M. C., & Viola, H. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1761-7_14 · Cited by 17
Protein Synthesis in Nerve Terminals and the Glia–Neuron Unit
Crispino, M., Cefaliello, C., Kaplan, B. B., & Giuditta, A. (2009) · Results and problems in cell differentiation · doi:10.1007/400_2009_9 · Cited by 16
The memory paradox
Yehuda, R., Joëls, M., & Morris, R. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2957 · Cited by 15
Anti-kindling Induced by Two-Stage Coordinated Reset Stimulation with Weak Onset Intensity
Zeitler, M., & Tass, P. A. (2016) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2016.00044 · Cited by 14
Differences Between Natural and Artificial Cognitive Systems
Singer, W. (2021) · Springer eBooks · doi:10.1007/978-3-030-54173-6_2 · Cited by 15
A Simplified Plasticity Model Based on Synaptic Tagging and Capture Theory: Simplified STC
Ding, Y., Wang, Y., & Cao, L. (2022) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2021.798418 · Cited by 14
“A well-known theory of conversion from early to latephase plasticity is synaptic tagging and capture (STC), which is supported by evidence both in vitro and in vivo (Frey and Morris, 1997; Redondo and Morris, 2011; Shires et al., 2012).”
Background
Towards a unified model of pavlovian conditioning: short review of trace conditioning models
Kryukov, V. I. (2012) · Cognitive Neurodynamics · doi:10.1007/s11571-012-9195-z · Cited by 15
“…rules are problematic for trace conditioning in view of the unsolved problem of shifting information from the hippocampus to the cortex (see Frey and Morris 1997; Lesburguères et al. 2011). the tapped delay-line stimulus processing is a neurobiologically plausible mechanism, especially…”
Background
NMDA receptor-dependent recruitment of calnexin to the neuronal plasma membrane
Itakura, M., Tsujimura, J., Yamamori, S., Ohkido, T., & Takahashi, M. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.06.064 · Cited by 15
Simulations suggest pharmacological methods for rescuing long-term potentiation
Smolen, P., Baxter, D. A., & Byrne, J. H. (2014) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2014.07.006 · Cited by 13
“PKA phosphorylation of an unspecified substrate is necessary to set a synaptic tag required for synaptic “capture” of proteins necessary for late LTP (Barco et al., 2002; Frey and Morris, 1997; Redondo and Morris, 2011).”
Background
Multifaceted role of nitric oxide in vascular dementia
Yang, Y., Ma, K., Li, S., & Xiong, T. (2025) · Medical Gas Research · doi:10.4103/mgr.medgasres-d-24-00158 · Cited by 13
Making Memories: Why Time Matters
Kelley, P., Evans, M. D. R., & Kelley, J. (2018) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2018.00400 · Cited by 10
Movement-dependent electrical stimulation for volitional strengthening of cortical connections in behaving monkeys
Moorjani, S., Walvekar, S., Fetz, E. E., & Perlmutter, S. I. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2116321119 · Cited by 9
Synaptic Tagging and Capture: From Synapses to Behavior
(2015) · doi:10.1007/978-1-4939-1761-7 · Cited by 19

Authors: Frey, U., & Morris, R. G. M.
ORCID: Morris, Richard G. M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1997-02
Volume: 385
Issue: 6616
Pages: 533-536
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/385533a0
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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