Cited by 1,736Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNeural dynamics and brain function

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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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Background
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“An attractive hypothesis, the synaptic tag hypothesis, was proposed by Frey and Morris (Frey & Morris, 1997, 1998) to explain the synapse speci®city of L-LTP.”
Background
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“It has also been proposed that synapses that express E-LTP are equipped with a ‘‘tag’’ that allows them to capture the essential proteins later on and so attain L-LTP properties (Frey and Morris, 1997; Barco et al., 2002).”
Background
Flexibility within working memory and the focus of attention for sequential verbal information does not depend on active maintenance
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Background
Differentiation in the protein synthesis-dependency of persistent synaptic plasticity in mossy fiber and associational/commissural CA3 synapses in vivo
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“This tag then could capture proteins after a subsequent attempt to induce synaptic plasticity, and support long-lasting modifications of the synapse (Frey and Morris, 1997, 1998; Martin et al., 1997; Casadio et al., 1999; Sajikumar and Frey, 2004; Sajikumar et al., 2007).”
Background
Structural Plasticity, Effectual Connectivity, and Memory in Cortex
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“Frontiers in Neuroanatomy | www.frontiersin.org 4 June 2016 | Volume 10 | Article 63 may identify the case Sij > 0 with tagging synapse ij for consolidation (Frey and Morris, 1997).”
Background
Behavioral and neural mechanisms by which prior experience impacts subsequent learning
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Schema‐like learning and memory consolidation acting through myelination
Hasan, M., Murugappan, S., Jun, W., Ramkrishnan, A. S., Iqbal, Z., Lee, Y., & Li, Y. (2019) · The FASEB Journal · doi:10.1096/fj.201900910r · Cited by 35
“What is the biologic basis of schema-like learning and memory consolidation in the HPC-ACC network? A model used for a memory mechanism of cellular consolidation research is synaptic tagging and capture, proposed by Frey and Morris (45), which stipulates that neural sig-”
Method
Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders
Knight, H. M., Öz, M. D., & PerezGrovas‐Saltijeral, A. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385858 · Cited by 33
“…Martinez De La Cruz et al. (2021) hypothesized that m 6 A mRNA methylation and demethylation by ALKBH5 is integral to a “synaptic tagging and capture” mechanism (Frey and Morris, 1997), i.e. a process proposed to explain how mRNAs are localized to, and available at, specifically activated synapses.”
Background
Optimal percentage of inhibitory synapses in multi-task learning
Capano, V., Herrmann, H. J., & de Arcangelis, L. (2015) · Scientific Reports · doi:10.1038/srep09895 · Cited by 35
“Conversely, if the response is wrong, we modify the strengths of those synapses active during the avalanche [23] by δg = ± α/d k , where d k is the chemical distance of each presynaptic neuron from the output neuron and α represents the strength of synaptic adaptation.”
Background
Post‐translational synaptic protein modification as substrate for long‐lasting, remote memory: An initial test
Holahan, M. R., & Routtenberg, A. (2006) · Hippocampus · doi:10.1002/hipo.20245 · Cited by 33
Lesioning the fimbria–fornix impairs basolateral amygdala induced reinforcement of LTP in the dentate gyrus
Jas, J., Almaguer, W., Frey, J. U., & Bergado, J. A. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02037-0 · Cited by 33
Synaptic Plasticity and Learning and Memory: 15 Years of Progress
Baudry, M. (1998) · Neurobiology of Learning and Memory · doi:10.1006/nlme.1998.3842 · Cited by 33
Behavior analysis and neuroscience: Complementary disciplines
Donahoe, J. W. (2017) · Journal of the Experimental Analysis of Behavior · doi:10.1002/jeab.251 · Cited by 34
“When the membrane potential becomes less negative, even if not enough to cause the postsynaptic neuron to “fire,” those specific AMPA receptors acquire a molecular “tag” that enhances their response to Glu for perhaps an hour or so (Frey, 1997; Frey & Morris, 1997).”
Background
Bidirectional manipulation of mTOR signaling disrupts socially mediated vocal learning in juvenile songbirds
Ahmadiantehrani, S., & London, S. E. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1701829114 · Cited by 31
Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines
Park, I., Kim, H. J., Kim, Y., Hwang, H. S., Kasai, H., Kim, J., & Park, J. W. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819374116 · Cited by 31
“The synaptic tagging, or capture, theory explains how particular synapses produce targets for subsequent trafficking of plasticityrelated proteins (PRPs) (41, 43) to achieve input-specific synaptic and structural plasticity.”
Background
The Quest for the Hippocampal Memory Engram: From Theories to Experimental Evidence
Miry, O., Li, J., & Chen, L. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.632019 · Cited by 40
“, early-LTP) into a long-lasting modification of synaptic strength (late-LTP) (Frey and Morris, 1997; Youngblood et al., 2010).”
Background
PKC regulates the δ2 glutamate receptor interaction with S-SCAM/MAGI-2 protein
Yap, C. C., Muto, Y., Kishida, H., Hashikawa, T., & Yano, R. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00070-6 · Cited by 32
Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampusPreprint
Connor, S. A., Hoeffer, C. A., Klann, E., & Nguyen, P. (2011) · Learning & Memory · doi:10.1101/lm.2043811 · Cited by 32
“ISSN 1549-5485/11; www.learnmem.org 207 Learning & Memory activity-dependent setting of “tags,” which capture plasticityrelated proteins (PRPs) necessary for expression of LTP (Frey and Morris 1997; for review, see Barco et al. 2008; Frey and Frey 2008).”
BackgroundMethodResultInfluential
Role of CPEB3 protein in learning and memory: new insights from synaptic plasticity
Qu, W., Sun, Q. H., Liu, Q. Q., Jin, H. J., Cui, R., Yang, W., Song, D. B., & Li, B. J. (2020) · Aging · doi:10.18632/aging.103404 · Cited by 31
Protein synthesis and consolidation of memory-related synaptic changes
LYNCH, G. S., Kramár, E. A., & Gall, C. M. (2014) · Brain Research · doi:10.1016/j.brainres.2014.11.060 · Cited by 31
“One way to test this hypothesis is to use a variation of the protocol that Frey and Morris (1997) developed to test their synaptic tag and capture hypothesis.”
MethodResult
Does semantic long-term memory impact refreshing in verbal working memory?
Camos, V., Mora, G., Oftinger, A.-L., Elsig, S. M., Schneider, P., & Vergauwe, E. (2018) · Journal of Experimental Psychology Learning Memory and Cognition · doi:10.1037/xlm0000657 · Cited by 36
Erythropoietin Promotes Neural Plasticity and Spatial Memory Recovery in Fimbria-Fornix-Lesioned Rats
Almaguer‐Melian, W., Mercerón‐Martínez, D., Fuentes, N. P., Alberti‐Amador, E., León-Martínez, R., Ledón, N., Delgado‐Ocaña, S., & Rosado, J. A. B. (2015) · Neurorehabilitation and neural repair · doi:10.1177/1545968315572389 · Cited by 31
“The time dependence of memory enhancing procedures or substances is well established(19) and can be explained at the cellular level by mechanisms of synaptic tagging.(41,42) According to this hypothesis, the activation of synaptic inputs sets a tag that can become reinforced from the capture and insertion of plasticit…”
BackgroundMethod
Temporal phases of long-term potentiation (LTP): myth or fact?
Abbas, A.-K., Villers, A., & Ris, L. (2015) · Reviews in the Neurosciences · doi:10.1515/revneuro-2014-0072 · Cited by 31
β-adrenergic signaling broadly contributes to LTP induction
Jędrzejewska‐Szmek, J., Luczak, V., Abel, T. G., & Blackwell, K. T. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005657 · Cited by 30
Capacitative Calcium Entry Induces Hippocampal Long Term Potentiation in the Absence of Presenilin-1
Ris, L., Dewachter, I., Reversé, D., Godaux, E., & LEUVEN, F. V. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300971200 · Cited by 31
Dopamine D1/D5 receptor signaling regulates synaptic cooperation and competition in hippocampal CA 1 pyramidal neurons via sustained ERK 1/2 activation
Shetty, M. S., Gopinadhan, S., & Sajikumar, S. (2015) · Hippocampus · doi:10.1002/hipo.22497 · Cited by 31
“As demonstrated recently, the midbrain dopaminergic neuron activity also promotes hippocampal network dynamics associated with memory persistence (McNamara et al., 2014).”
Background
Behavioral, cellular, and synaptic tagging frameworks
Nomoto, M., & Inokuchi, K. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.03.010 · Cited by 31
Behavioral tagging and capture: long-term memory decline in middle-aged rats
Gros, A., & Wang, S. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.02.023 · Cited by 30
“It is proposed that in aged neural networks, there is a reduction of PRPs and that therefore, due to competition, PRPs are only used by the strongly stimulated synapses as they cannot not be captured by the weakly stimulated synapses (Sharma et al., 2015).”
Influential
Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal
Sossin, W. S. (2018) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2018.00005 · Cited by 31
“In models of synaptic tagging, the learning stimuli result in the formation of tags at activated synapses that then capture the products of gene expression in order to change the strength of the synapse (Frey and Morris, 1997, 1998a; Martin et al., 1997).”
Background
Activation of microglia in acute hippocampal slices affects activity-dependent long-term potentiation and synaptic tagging and capture in area CA1
Raghuraman, R., Karthikeyan, A., Wei, W. L., Dheen, S. T., & Sajikumar, S. (2019) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2019.107039 · Cited by 32
Neural correlates of sleep, stress, and selective memory consolidation
Kim, S. Y., & Payne, J. D. (2020) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2019.12.009 · Cited by 33
Exploration of a novel virtual environment improves memory consolidation in ADHD
Baumann, V., Birnbaum, T., Breitling-Ziegler, C., Tegelbeckers, J., Dambacher, J., Edelmann, E., Bergado-Acosta, J. R., Flechtner, H., & Krauel, K. (2020) · Scientific Reports · doi:10.1038/s41598-020-78222-4 · Cited by 33
The dendritic engram
Kastellakis, G., Tasciotti, S., Pandi, I., & Poirazi, P. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2023.1212139 · Cited by 36
Cell-type-specific optogenetic stimulation of the locus coeruleus induces slow-onset potentiation and enhances everyday memory in rats
Tse, D., Privitera, L., Norton, A. C., Gobbo, F., Spooner, P. A., Takeuchi, T., Martin, S. J., & Morris, R. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307275120 · Cited by 31
“Guided by the synaptic tagging and capture (STC) hypothesis of cellular consolidation (6, 7), in vitro electrophysiological studies have established that strong afferent tetanic stimulation of glutamatergic and neuromodulatory inputs to the CA1 region of the hippocampus not only produces a long -…”
Overexpression of PKMζ Alters Morphology and Function of Dendritic Spines in Cultured Cortical Neurons
Ron, S., Dudai, Y., & Segal, M. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhr323 · Cited by 30
“…result and the aforementioned morphological effects are in line with the hypothesis that newly synthesized PKMf locates preferentially to specific preexisting synapses through a potential ''synaptic tagging'' mechanism (Sossin 1996; Frey and Morris 1997; Sajikumar et al. 2005; Shema et al. 2011).”
Background
Optimal percentage of inhibitory synapses in multi-task learning
Capano, V., Herrmann, H. J., & de Arcangelis, L. (2015) · Repository for Publications and Research Data (ETH Zurich) · doi:10.3929/ethz-b-000101080 · Cited by 30

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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Synaptic tagging and long-term potentiation

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