The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Protein Synthesis Is Required for the Enhancement of Long-Term Potentiation and Long-Term Memory by Spaced Training
Abstract
Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“LTP that persists for several hours or more requires translation and transcription50,51, which is reliant on key transcription factors such as cyclic AMP-responsive element (CRE)-binding protein (CREB)52.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [51]
Citations
Cites
A synaptic model of memory: long-term potentiation in the hippocampus
Bliss, T. V. P., & Collingridge, G. L. (1993) · Nature · doi:10.1038/361031a0 · Cited by 11,566
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444
Bienenstock, E., Cooper, L., & Munro, P. (1982) · The Journal of Neuroscience · doi:10.1523/jneurosci.02-01-00032.1982 · Cited by 2,896
Synaptic Plasticity and Memory: An Evaluation of the Hypothesis
Martin, S. J., Grimwood, P. D., & Morris, R. G. M. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.649 · Cited by 2,794
Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat.
Barnes, C. A. (1979) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077579 · Cited by 2,088
Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G., & Silva, A. J. (1994) · Cell · doi:10.1016/0092-8674(94)90400-6 · Cited by 1,800
Protein synthesis and memory: A review.
Davis, H. P., & Squire, L. R. (1984) · Psychological Bulletin · doi:10.1037/0033-2909.96.3.518 · Cited by 1,505
Abel, T., Nguyen, P. V., Barad, M., Deuel, T. A. S., Kandel, E. R., & Bourtchouladze, R. (1997) · Cell · doi:10.1016/s0092-8674(00)81904-2 · Cited by 1,217
Self-citationThe MAPK cascade is required for mammalian associative learning
Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M., & Sweatt, J. D. (1998) · Nature Neuroscience · doi:10.1038/2836 · Cited by 1,083
Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila
Yin, J. C. P., Wallach, J. S., Del Vecchio, M., Wilder, E. L., Zhou, H., Quinn, W. G., & Tully, T. (1994) · Cell · doi:10.1016/0092-8674(94)90399-9 · Cited by 959
Jones, M. W., Errington, M. L., French, P. J., Fine, A., Bliss, T., Garel, S., Charnay, P., Bozon, B., Laroche, S., & Davis, S. (2001) · Nature Neuroscience · doi:10.1038/85138 · Cited by 925
Genetic dissection of consolidated memory in Drosophila
Tully, T., Preat, T., Boynton, S. C., & Del Vecchio, M. (1994) · Cell · doi:10.1016/0092-8674(94)90398-0 · Cited by 924
Impey, S., Obrietan, K. H., Wong, S. T., Poser, S., Yano, S., Wayman, G. A., Deloulme, J., Chan, G. C. ‐., & Storm, D. R. (1998) · Neuron · doi:10.1016/s0896-6273(00)80602-9 · Cited by 895
Requirement of a Critical Period of Transcription for Induction of a Late Phase of LTP
Nguyen, P. V., Abel, T., & Kandel, E. R. (1994) · Science · doi:10.1126/science.8066450 · Cited by 888
Self-citationA Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation
English, J. D., & Sweatt, J. D. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19103 · Cited by 860
Frey, U., Krug, M., Reymann, K. G., & Matthies, H. (1988) · Brain Research · doi:10.1016/0006-8993(88)90008-x · Cited by 806
Behavioral studies of Pavlovian conditioning
Rescorla, R. A. (1988) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.11.030188.001553 · Cited by 715
Yin, J. C. P., Del Vecchio, M., Zhou, H., & Tully, T. (1995) · Cell · doi:10.1016/0092-8674(95)90375-5 · Cited by 642
Bach, M. E., Barad, M., Son, H., Zhuo, M., Lü, Y.-F., Shih, R., Mansuy, I. M., Hawkins, R. D., & Kandel, E. R. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.9.5280 · Cited by 571
Mayford, M., Wang, J., Kandel, E., & O'Dell, T. (1995) · Cell · doi:10.1016/0092-8674(95)90009-8 · Cited by 552
Roberson, E. D., English, J. D., Adams, J. P., Selcher, J. C., Kondratick, C. M., & Sweatt, J. D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-11-04337.1999 · Cited by 544
Bourtchouladze, R., Abel, T., Berman, N., Gordon, R., Lapidus, K., & Kandel, E. R. (1998) · Learning & Memory · doi:10.1101/lm.5.4.365 · Cited by 525
Self-citationJosselyn, S. A., Shi, C., Carlezon, W. A., Neve, R. L., Nestler, E. J., & Davis, M. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-07-02404.2001 · Cited by 451
Schafe, G. E., Nadel, N. V., Sullivan, G. M., Harris, A. Z., & LeDoux, J. E. (1999) · Learning & Memory · doi:10.1101/lm.6.2.97 · Cited by 413
Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology
Wu, G., Deisseroth, K. A., & Tsien, R. W. (2001) · Nature Neuroscience · doi:10.1038/83976 · Cited by 397
Hippocampus and context in classical conditioning
Holland, P. C., & Bouton, M. E. (1999) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(99)80027-0 · Cited by 394
Theoretical Implications of the Spacing Effect 1
Hintzman, D. L. (2024) · Routledge eBooks · doi:10.4324/9781032722375-5 · Cited by 364
Spaced training induces normal long-term memory in CREB mutant mice
Kogan, J. H., Frankland, P. W., Blendy, J. A., Coblentz, J., Marowitz, Z., Schütz, G., & Silva, A. J. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00022-4 · Cited by 350
Targeting of the CREB gene leads to up‐regulation of a novel CREB mRNA isoform.
Blendy, J. A., Kaestner, K. H., Schmid, W., Gass, P., & Schütz, G. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00447.x · Cited by 223
The influence of duration of protein synthesis inhibition on memory
Flood, J. F., Rosenzweig, M. R., Bennett, E. L., & Orme, A. E. (1973) · Physiology & Behavior · doi:10.1016/0031-9384(73)90221-7 · Cited by 216
Deficits in Memory Tasks of Mice with CREB Mutations Depend on Gene DosagePreprint
Gass, P., Wolfer, D. P., Balschun, D., Rudolph, D., Frey, U., Lipp, H.-P., & Schütz, G. (1998) · Learning & Memory · doi:10.1101/lm.5.4.274 · Cited by 208
Ebbinghaus, H. (1996) · University of Toronto eBooks · Cited by 203
Trial and intertrial durations in Pavlovian conditioning: Issues of learning and performance.
Lattal, K. M. (1999) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037/0097-7403.25.4.433 · Cited by 112
Self-citationBehavioral analysis of CREB αΔ mutation on a B6/129 F1 hybrid background
Graves, L. A., Dalvi, A., Lucki, I., Blendy, J. A., & Abel, T. G. (2002) · Hippocampus · doi:10.1002/hipo.10003 · Cited by 108
Self-citationDoyère, V., & Laroche, S. (1992) · Hippocampus · doi:10.1002/hipo.450020106 · Cited by 101
Rammes, G., Steckler, T., Kresse, A. E., Schütz, G., Zieglgänsberger, W., & Lutz, B. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00108.x · Cited by 100
Nguyen, P., Duffy, S. N., & Young, J. Z. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.84.5.2484 · Cited by 88
Self-citationWoo, N. H., Duffy, S. N., Abel, T. G., & Nguyen, P. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.84.6.2739 · Cited by 47
Self-citationMemory: Old questions, new perspectives
Eichenbaum, H. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00021-2 · Cited by 14
Research works printed but not linked: 2
- Pittenger C, 2000, Soc Neurosci Abstr, 26, 1509
- Woo NH, 2000, Soc Neurosci Abstr, 26, 355
Cited by
Sorted by citations
Optimizing inhibitory learning during exposure therapy
Craske, M. G., Kircanski, K., Zelikowsky, M., Mystkowski, J., Chowdhury, N., & Baker, A. (2008) · Behaviour Research and Therapy · doi:10.1016/j.brat.2007.10.003 · Cited by 1,607
BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory?
Lü, Y., Christian, K. M., & Lu, B. (2007) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2007.08.018 · Cited by 807
Bekinschtein, P., Cammarota, M., Igaz, L. M., Bevilaqua, L. R. M., Izquierdo, I., & Medina, J. H. (2007) · Neuron · doi:10.1016/j.neuron.2006.11.025 · Cited by 633
Cascade Models of Synaptically Stored Memories
Fusi, S., Drew, P. J., & Abbott, L. F. (2005) · Neuron · doi:10.1016/j.neuron.2005.02.001 · Cited by 569
Translational 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
Metadata
- Authors
- Scharf, M. T., Woo, N. H., Lattal, K. M., Young, J. Z., Nguyen, P. V., & Abel, T.
- Affiliations
- University of Pennsylvania (US)
- Physiology and
- Department of Biology and
- University of Alberta (CA)
- Venue
- Journal of Neurophysiology
- Publisher
- American Physiological Society
- Published
- 2002-06-01
- Volume
- 87
- Issue
- 6
- Pages
- 2770-2777
- ISSN
- 0022-3077 (ISSN-L)
- 1522-1598
- OpenAlex
- W2259231394
- Cited by
- 204
- References
- 39
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 9 · 2017: 6 · 2016: 11 · 2015: 9 · 2014: 11 · 2013: 13 · 2012: 8
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurophysiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG18199, R01AG018199)
- National Institute of Mental Health (R01MH060244, MH 60244)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD026979, HD 26979)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- spaced training, massed training, long-term potentiation, protein synthesis, long-term memory, contextual fear conditioning, hippocampus, synaptic plasticity, anisomycin, memory consolidation
- MeSH terms
- Animals, Anisomycin, Conditioning, Psychological, Electric Stimulation, Fear, Female, Hippocampus, Male, Memory, Mice, Inbred C57BL, Organ Culture Techniques, Protein Synthesis Inhibitors, Synapses, Long-Term Potentiation, Excitatory Postsynaptic Potentials, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
