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Making memories last: the synaptic tagging and capture hypothesis

Key Points

  • The fate of a memory is not determined at the time of encoding, and this can be explained by the susceptibility of synaptic plasticity to modulation around the time of induction.

  • The synaptic tagging and capture (STC) hypothesis explains this by dissociating synapse-specific tagging from diffusible plasticity-related products (PRPs) — that is, proteins and mRNAs.

  • Recent findings suggest that the induction of the tagged state can be independent of the expression of long-term potentiation (LTP) itself, and this can be explained by differences in the mechanisms of structural and functional plasticity. In this way, experiments targeting structural plasticity block tagging while allowing the expression of LTP.

  • Taking this into account, the STC can contribute to the understanding of a series of electrophysiological and behavioural phenomena ranging from synaptic plasticity to reconsolidation. For example, slow-onset plasticity is explained through tagging without immediate expression, whereby LTP develops as PRPs are captured by non-potentiated but tagged synapses.

  • Behaviourally, weak encoding protocols achieve long-term memory if PRPs are made available by an unrelated event before or after encoding.

Abstract

The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.

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Figure 1: The synaptic tagging and capture (STC) hypothesis and its challenges.
Figure 2: The dissociation of LTP expression and synaptic tagging.
Figure 3: A distinction between structural and functional plasticity.
Figure 4: The revised STC hypothesis — molecular events associated with induction of E-LTP and L-LTP.
Figure 5: Synaptic tagging and capture.
Figure 6: Behavioural correlates of synaptic tagging and capture.

References

  1. Ramon y Cajal, S. Textura del Sistema Nervioso del Hombre y de los Vertebrados: Estudios Sobre el Plan Estructural y Composición Histológica de los Centros Nerviosos Adicionados de Consideraciones Fisiológicas Fundadas en los Nuevos Descubrimentos (Moya, Madrid, 1899).

    Google Scholar 

  2. Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (Wiley, Chapman & Hall, New York, London, 1949).

    Google Scholar 

  3. Goelet, P., Castellucci, V. F., Schacher, S. & Kandel, E. R. The long and the short of long-term memory — a molecular framework. Nature 322, 419–422 (1986).

    CAS  PubMed  Google Scholar 

  4. Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).

    CAS  PubMed  Google Scholar 

  5. Dayan, P. & Abbott, L. F. Theoretical Neuroscience: Computational and Mathematical Modeling of Neural Systems (MIT Press, Cambridge, Mass., 2001).

    Google Scholar 

  6. Dudai, Y. & Morris, R. G. M. in Brain, Perception, Memory: Advances in Cognitive Neuroscience (ed. Bolhuis, J. J.) 149–162 (Oxford University Press, New York, 2000). A review that introduced the distinction between the concepts of cellular and systems consolidation.

    Google Scholar 

  7. Nader, K., Schafe, G. E. & LeDoux, J. E. The labile nature of consolidation theory. Nature Rev. Neurosci. 1, 216–219 (2000).

    CAS  Google Scholar 

  8. Sara, S. J. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn. Mem. 7, 73–84 (2000).

    CAS  PubMed  Google Scholar 

  9. Lee, J. L. Reconsolidation: maintaining memory relevance. Trends Neurosci. 32, 413–420 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nadel, L. & Moscovitch, M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227 (1997).

    CAS  PubMed  Google Scholar 

  11. Squire, L. R. & Bayley, P. J. The neuroscience of remote memory. Curr. Opin. Neurobiol. 17, 185–196 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Tse, D. et al. Schemas and memory consolidation. Science 316, 76–82 (2007).

    CAS  PubMed  Google Scholar 

  13. Frankland, P. W. & Bontempi, B. The organization of recent and remote memories. Nature Rev. Neurosci. 6, 119–130 (2005).

    CAS  Google Scholar 

  14. Barnes, C. A. & McNaughton, B. L. An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behav. Neurosci. 99, 1040–1048 (1985).

    CAS  PubMed  Google Scholar 

  15. Barrett, A. B., Billings, G. O., Morris, R. G. & van Rossum, M. C. State based model of long-term potentiation and synaptic tagging and capture. PLoS Comput. Biol. 5, e1000259 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. Clopath, C., Ziegler, L., Vasilaki, E., Busing, L. & Gerstner, W. Tag–trigger–consolidation: a model of early and late long-term-potentiation and depression. PLoS Comput. Biol. 4, e1000248 (2008).

    PubMed  PubMed Central  Google Scholar 

  17. Frey, U. & Morris, R. G. M. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997). The first demonstration of the phenomenon of synaptic tagging.

    CAS  PubMed  Google Scholar 

  18. Frey, U. & Morris, R. G. M. Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181–188 (1998).

    CAS  PubMed  Google Scholar 

  19. Kandel, E. R., Schwartz, J. H. & Jessell, T. Principles of Neural Science (McGraw-Hill Medical, 2000).

    Google Scholar 

  20. Reymann, K. G. & Frey, J. U. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications. Neuropharmacology 52, 24–40 (2007).

    CAS  PubMed  Google Scholar 

  21. Barco, A., Lopez de Armentia, M. & Alarcon, J. M. Synapse-specific stabilization of plasticity processes: the synaptic tagging and capture hypothesis revisited 10 years later. Neurosci. Biobehav Rev. 32, 831–851 (2008).

    PubMed  Google Scholar 

  22. Zhou, Q. & Poo, M. M. Reversal and consolidation of activity-induced synaptic modifications. Trends Neurosci. 27, 378–383 (2004).

    CAS  PubMed  Google Scholar 

  23. Lynch, G., Rex, C. S. & Gall, C. M. LTP consolidation: substrates, explanatory power, and functional significance. Neuropharmacology 52, 12–23 (2007).

    CAS  PubMed  Google Scholar 

  24. Sajikumar, S. & Frey, J. U. Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD. Neurobiol. Learn. Mem. 82, 12–25 (2004).

    CAS  PubMed  Google Scholar 

  25. Steward, O. & Fass, B. Polyribosomes associated with dendritic spines in the denervated dentate gyrus: evidence for local regulation of protein synthesis during reinnervation. Prog. Brain Res. 58, 131–136 (1983).

    CAS  PubMed  Google Scholar 

  26. Kang, H. & Schuman, E. M. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273, 1402–1406 (1996).

    CAS  PubMed  Google Scholar 

  27. Casadio, A. et al. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99, 221–237 (1999).

    CAS  PubMed  Google Scholar 

  28. Mayford, M., Baranes, D., Podsypanina, K. & Kandel, E. R. The 3′-untranslated region of CaMKII alpha is a cis-acting signal for the localization and translation of mRNA in dendrites. Proc. Natl Acad. Sci. USA 93, 13250–13255 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kelleher, R. J. 3rd, Govindarajan, A. & Tonegawa, S. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 59–73 (2004).

    CAS  PubMed  Google Scholar 

  30. Lanahan, A. & Worley, P. Immediate-early genes and synaptic function. Neurobiol. Learn. Mem. 70, 37–43 (1998).

    CAS  PubMed  Google Scholar 

  31. Miyashita, T., Kubik, S., Lewandowski, G. & Guzowski, J. F. Networks of neurons, networks of genes: an integrated view of memory consolidation. Neurobiol. Learn. Mem. 89, 269–284 (2008).

    CAS  PubMed  Google Scholar 

  32. Wang, D. O., Martin, K. C. & Zukin, R. S. Spatially restricting gene expression by local translation at synapses. Trends Neurosci. 33, 173–182 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Fonseca, R., Nagerl, U. V., Morris, R. G. M. & Bonhoeffer, T. Competing for memory: hippocampal LTP under regimes of reduced protein synthesis. Neuron 44, 1011–1020 (2004). An intriguing finding, which might occur physiologically, in which competition for PRPs results in competitive rather than synergistic interactions between sets of synapses.

    CAS  PubMed  Google Scholar 

  34. Ramachandran, B. & Frey, J. U. Interfering with the actin network and its effect on long-term potentiation and synaptic tagging in hippocampal CA1 neurons in slices in vitro. J. Neurosci. 29, 12167–12173 (2009). The authors combined weak and strong stimulation of independent pathways to show the necessary role of reconfiguration of the cytoskeleton in synaptic tagging but not in PRP availability.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Redondo, R. L. et al. Synaptic tagging and capture: differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation. J. Neurosci. 30, 4981–4989 (2010). This study dissected the necessary role of CaMKII in tagging from the necessary role of CaMKIV in making PRPs available, and showed that untagged synapses can still express LTP for hours.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bashir, Z. I. & Collingridge, G. L. An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus. Exp. Brain Res. 79, 437–443 (1994).

    Google Scholar 

  37. Staubli, U. & Chun, D. Factors regulating the reversibility of long-term potentiation. J. Neurosci. 16, 853–860 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Martin, S. J. Time-dependent reversal of dentate LTP by 5 Hz stimulation. Neuroreport 9, 3775–3781 (1998).

    CAS  PubMed  Google Scholar 

  39. Sajikumar, S. & Frey, J. U. Resetting of 'synaptic tags' is time- and activity-dependent in rat hippocampal CA1 in vitro. Neuroscience 129, 503–507 (2004).

    CAS  PubMed  Google Scholar 

  40. Sajikumar, S., Li, Q., Abraham, W. C. & Xiao, Z. C. Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1. Learn. Mem. 16, 178–186 (2009).

    PubMed  Google Scholar 

  41. Navakkode, S., Sajikumar, S. & Frey, J. U. Synergistic requirements for the induction of dopaminergic D1/D5-receptor-mediated LTP in hippocampal slices of rat CA1 in vitro. Neuropharmacology 52, 1547–1554 (2007).

    CAS  PubMed  Google Scholar 

  42. Aniksztejn, L. & Ben-Ari, Y. Novel form of long-term potentiation produced by a K+ channel blocker in the hippocampus. Nature 349, 67–69 (1991).

    CAS  PubMed  Google Scholar 

  43. Wieraszko, A., Li, G., Kornecki, E., Hogan, M. V. & Ehrlich, Y. H. Long-term potentiation in the hippocampus induced by platelet-activating factor. Neuron 10, 553–557 (1993).

    CAS  PubMed  Google Scholar 

  44. Auerbach, J. M. & Segal, M. A novel cholinergic induction of long-term potentiation in rat hippocampus. J. Neurophysiol. 72, 2034–2040 (1994).

    CAS  PubMed  Google Scholar 

  45. Messaoudi, E., Ying, S. W., Kanhema, T., Croll, S. D. & Bramham, C. R. Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. J. Neurosci. 22, 7453–7461 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Isaac, J. T., Buchanan, K. A., Muller, R. U. & Mellor, J. R. Hippocampal place cell firing patterns can induce long-term synaptic plasticity in vitro. J. Neurosci. 29, 6840–6850 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).

    CAS  PubMed  Google Scholar 

  48. Zhou, Q., Homma, K. J. & Poo, M. M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757 (2004).

    CAS  PubMed  Google Scholar 

  49. Kopec, C. D., Li, B., Wei, W., Boehm, J. & Malinow, R. Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation. J. Neurosci. 26, 2000–2009 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Cingolani, L. A. & Goda, Y. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nature Rev. Neurosci. 9, 344–356 (2008).

    CAS  Google Scholar 

  51. Bramham, C. R. Local protein synthesis, actin dynamics, and LTP consolidation. Curr. Opin. Neurobiol. 18, 524–531 (2008).

    CAS  PubMed  Google Scholar 

  52. Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

    CAS  PubMed  Google Scholar 

  53. Esteban, J. A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nature Neurosci. 6, 136–143 (2003).

    CAS  PubMed  Google Scholar 

  54. Antonova, I. et al. Rapid increase in clusters of presynaptic proteins at onset of long-lasting potentiation. Science 294, 1547–1550 (2001).

    CAS  PubMed  Google Scholar 

  55. Kullmann, D. M. & Nicoll, R. A. Long-term potentiation is associated with increases in quantal content and quantal amplitude. Nature 357, 240–244 (1992).

    CAS  PubMed  Google Scholar 

  56. Kopec, C. D., Real, E., Kessels, H. W. & Malinow, R. GluR1 links structural and functional plasticity at excitatory synapses. J. Neurosci. 27, 13706–13718 (2007). The results show a necessary structural role for AMPAR incorporation in the maintenance but not the initial phases of the structural expansion underlying LTP.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Yang, Y., Wang, X. B., Frerking, M. & Zhou, Q. Spine expansion and stabilization associated with long-term potentiation. J. Neurosci. 28, 5740–5751 (2008). This paper demonstrates the dissociation between functional LTP and structural plasticity, and suggests that the time-sensitive block of spine expansion by phosphatases might underlie tag resetting.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, X. B., Yang, Y. & Zhou, Q. Independent expression of synaptic and morphological plasticity associated with long-term depression. J. Neurosci. 27, 12419–12429 (2007). By monitoring spine size and synaptic responses, this study reveals a dissociation between the functional expression and structural plasticity of LTD, supporting other studies showing independent but parallel kinase and phosphatase pathways responsible for long-term plasticity.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hotulainen, P. & Hoogenraad, C. C. Actin in dendritic spines: connecting dynamics to function. J. Cell Biol. 189, 619–629 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Okamoto, K., Narayanan, R., Lee, S. H., Murata, K. & Hayashi, Y. The role of CaMKII as an F-actin-bundling protein crucial for maintenance of dendritic spine structure. Proc. Natl Acad. Sci. USA 104, 6418–6423 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Honkura, N., Matsuzaki, M., Noguchi, J., Ellis-Davies, G. C. & Kasai, H. The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57, 719–729 (2008).

    CAS  PubMed  Google Scholar 

  62. Okamoto, K., Bosch, M. & Hayashi, Y. The roles of CaMKII and F-actin in the structural plasticity of dendritic spines: a potential molecular identity of a synaptic tag? Physiology (Bethesda) 24, 357–366 (2009). A review of the interaction between CaMKII and actin in structural plasticity and tagging.

    CAS  Google Scholar 

  63. Okamoto, K., Nagai, T., Miyawaki, A. & Hayashi, Y. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nature Neurosci. 7, 1104–1112 (2004).

    CAS  PubMed  Google Scholar 

  64. Lin, B. et al. Theta stimulation polymerizes actin in dendritic spines of hippocampus. J. Neurosci. 25, 2062–2069 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lang, C. et al. Transient expansion of synaptically connected dendritic spines upon induction of hippocampal long-term potentiation. Proc. Natl Acad. Sci. USA 101, 16665–16670 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Toni, N. et al. Remodeling of synaptic membranes after induction of long-term potentiation. J. Neurosci. 21, 6245–6251 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Geinisman, Y., de Toledo-Morrell, L. & Morrell, F. Induction of long-term potentiation is associated with an increase in the number of axospinous synapses with segmented postsynaptic densities. Brain Res. 566, 77–88 (1991). A classical finding showing that long-term structural changes can include the splitting of an individual synapse into two.

    CAS  PubMed  Google Scholar 

  68. Sajikumar, S., Navakkode, S. & Frey, J. U. Identification of compartment- and process-specific molecules required for “synaptic tagging” during long-term potentiation and long-term depression in hippocampal CA1. J. Neurosci. 27, 5068–5080 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Giese, K. P., Fedorov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998).

    CAS  PubMed  Google Scholar 

  70. Sanhueza, M., McIntyre, C. C. & Lisman, J. E. Reversal of synaptic memory by Ca2+/calmodulin-dependent protein kinase II inhibitor. J. Neurosci. 27, 5190–5199 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ling, D. S., Benardo, L. S. & Sacktor, T. C. Protein kinase Mzeta enhances excitatory synaptic transmission by increasing the number of active postsynaptic AMPA receptors. Hippocampus 16, 443–452 (2006).

    CAS  PubMed  Google Scholar 

  72. Yao, Y. et al. PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J. Neurosci. 28, 7820–7827 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sajikumar, S., Navakkode, S., Sacktor, T. C. & Frey, J. U. Synaptic tagging and cross-tagging: the role of protein kinase Mzeta in maintaining long-term potentiation but not long-term depression. J. Neurosci. 25, 5750–5756 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Pastalkova, E. et al. Storage of spatial information by the maintenance mechanism of LTP. Science 313, 1141–1144 (2006).

    CAS  PubMed  Google Scholar 

  75. Lisman, J. & Raghavachari, S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci. STKE 2006, re11 (2006). A groundbreaking model explaining the link between postsynaptic receptor incorporation into PSD slots and presynaptic modifications in vesicle release.

    PubMed  Google Scholar 

  76. Martin, K. C. & Kosik, K. S. Synaptic tagging — who's it? Nature Rev. Neurosci. 3, 813–820 (2002).

    CAS  Google Scholar 

  77. Frey, U. & Morris, R. G. M. Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP. Neuropharmacology 37, 545–552 (1998).

    CAS  PubMed  Google Scholar 

  78. Yamauchi, T. & Fujisawa, H. Self-regulation of calmodulin-dependent protein kinase II and glycogen synthase kinase by autophosphorylation. Biochem. Biophys. Res. Commun. 129, 213–219 (1985).

    CAS  PubMed  Google Scholar 

  79. Yoshimura, Y. & Yamauchi, T. Phosphorylation-dependent reversible association of Ca2+/calmodulin-dependent protein kinase II with the postsynaptic densities. J. Biol. Chem. 272, 26354–26359 (1997).

    CAS  PubMed  Google Scholar 

  80. Shen, K. & Meyer, T. Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 284, 162–166 (1999).

    CAS  PubMed  Google Scholar 

  81. Strack, S., Barban, M. A., Wadzinski, B. E. & Colbran, R. J. Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J. Neurochem. 68, 2119–28 (1997).

    CAS  PubMed  Google Scholar 

  82. Yoshimura, Y., Sogawa, Y. & Yamauchi, T. Protein phosphatase 1 is involved in the dissociation of Ca2+/calmodulin-dependent protein kinase II from postsynaptic densities. FEBS Lett. 446, 239–242 (1999).

    CAS  PubMed  Google Scholar 

  83. Bayer, K. U., De Koninck, P., Leonard, A. S., Hell, J. W. & Schulman, H. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411, 801–805 (2001).

    CAS  PubMed  Google Scholar 

  84. Bayer, K. U. et al. Transition from reversible to persistent binding of CaMKII to postsynaptic sites and NR2B. J. Neurosci. 26, 1164–74 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Strack, S., Choi, S., Lovinger, D. M. & Colbran, R. J. Translocation of autophosphorylated calcium/calmodulin-dependent protein kinase II to the postsynaptic density. J. Biol. Chem. 272, 13467–13470 (1997).

    CAS  PubMed  Google Scholar 

  86. Lisman, J. E. Long-term potentiation: outstanding questions and attempted synthesis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 829–842 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Luscher, C., Nicoll, R. A., Malenka, R. C. & Muller, D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nature Neurosci. 3, 545–550 (2000).

    CAS  PubMed  Google Scholar 

  88. Woo, N. H., Abel, T. & Nguyen, P. V. Genetic and pharmacological demonstration of a role for cyclic AMP-dependent protein kinase-mediated suppression of protein phosphatases in gating the expression of late LTP. Eur. J. Neurosci. 16, 1871–1876 (2002).

    PubMed  Google Scholar 

  89. Nguyen, P. V. & Woo, N. H. Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases. Prog. Neurobiol. 71, 401–437 (2003).

    CAS  PubMed  Google Scholar 

  90. Young, J. Z., Isiegas, C., Abel, T. & Nguyen, P. V. Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging. Eur. J. Neurosci. 23, 1784–1794 (2006).

    PubMed  PubMed Central  Google Scholar 

  91. Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

    CAS  PubMed  Google Scholar 

  92. Wang, H. et al. CaMKII activation state underlies synaptic labile phase of LTP and short-term memory formation. Curr. Biol. 18, 1546–1554 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Liao, L. et al. BDNF induces widespread changes in synaptic protein content and up-regulates components of the translation machinery: an analysis using high-throughput proteomics. J. Proteome Res. 6, 1059–1071 (2007).

    CAS  PubMed  Google Scholar 

  94. Hetman, M., Kanning, K., Cavanaugh, J. E. & Xia, Z. Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 22569–22580 (1999).

    CAS  PubMed  Google Scholar 

  95. Rex, C. S. et al. Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J. Neurosci. 27, 3017–3029 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yoshii, A. & Constantine-Paton, M. BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation. Nature Neurosci. 10, 702–11 (2007).

    CAS  PubMed  Google Scholar 

  97. Ji, Y. et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nature Neurosci. 13, 302–309 (2010).

    CAS  PubMed  Google Scholar 

  98. Takemoto-Kimura, S. et al. Regulation of dendritogenesis via a lipid-raft-associated Ca2+/calmodulin-dependent protein kinase CLICK-III/CaMKIg. Neuron 54, 755–770 (2007).

    CAS  PubMed  Google Scholar 

  99. Bekinschtein, P. et al. Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 53, 261–277 (2007).

    CAS  PubMed  Google Scholar 

  100. Tanaka, J.-i. et al. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319, 1683–1687 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Kemp, A. & Manahan-Vaughan, D. Hippocampal long-term depression and long-term potentiation encode different aspects of novelty acquisition. Proc. Natl Acad. Sci. USA 101, 8192–8197 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Seidenbecher, T., Reymann, Klaus G. & Balschun, D. A post-tetanic time window for the reinforcement of long-term potentiation by appetitive and aversive stimuli. Proc. Natl Acad. Sci. USA 94, 1494–1499 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

    CAS  PubMed  Google Scholar 

  104. Guzowski, J. F., McNaughton, B. L., Barnes, C. A. & Worley, P. F. Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nature Neurosci. 2, 1120–1124 (1999).

    CAS  PubMed  Google Scholar 

  105. Moncada, D. & Viola, H. Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging. J. Neurosci. 27, 7476–7481 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ballarini, F., Moncada, D., Martinez, M. C., Alen, N. & Viola, H. Behavioral tagging is a general mechanism of long-term memory formation. Proc. Natl Acad. Sci. USA 106, 14599–14604 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Merhav, M. & Rosenblum, K. Facilitation of taste memory acquisition by experiencing previous novel taste is protein-synthesis dependent. Learn. Mem. 15, 501–507 (2008).

    PubMed  PubMed Central  Google Scholar 

  108. Wang, S.-H., Redondo, R. L. & Morris, R. G. M. Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. Proc. Natl Acad. Sci. USA 107, 19537–19542 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lisman, J. E. & Grace, A. A. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46, 703–713 (2005).

    CAS  PubMed  Google Scholar 

  110. McGaugh, J. L. Memory — a century of consolidation. Science 287, 248–251 (2000).

    CAS  PubMed  Google Scholar 

  111. Nader, K., Schafe, G. E. & Le Doux, J. E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).

    CAS  PubMed  Google Scholar 

  112. Lee, S. H. et al. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256 (2008). The authors showed that, during the retrieval of contextual fear memory, the amnesic effect of protein synthesis inhibitors can be prevented by inhibiting protein degradation by the proteasome, suggesting that synaptic engrams encoding memories are routinely destabilized and restabilized.

    CAS  PubMed  Google Scholar 

  113. Cai, F., Frey, J., Sanna, P. & Behnisch, T. Protein degradation by the proteasome is required for synaptic tagging and the heterosynaptic stabilization of hippocampal late-phase LTP. Neuroscience 169, 1520–1526 (2010).

    CAS  PubMed  Google Scholar 

  114. Kaang, B. K., Lee, S. H. & Kim, H. Synaptic protein degradation as a mechanism in memory reorganization. Neuroscientist 15, 430–435 (2009).

    PubMed  Google Scholar 

  115. Karpova, A., Mikhaylova, M., Thomas, U., Knopfel, T. & Behnisch, T. Involvement of protein synthesis and degradation in long-term potentiation of Schaffer collateral CA1 synapses. J. Neurosci. 26, 4949–4955 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lopez-Salon, M. et al. The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur. J. Neurosci. 14, 1820–1826 (2001).

    CAS  PubMed  Google Scholar 

  117. Hegde, A. N. Ubiquitin-proteasome-mediated local protein degradation and synaptic plasticity. Prog. Neurobiol. 73, 311–357 (2004).

    CAS  PubMed  Google Scholar 

  118. Fonseca, R., Vabulas, R. M., Hartl, F. U., Bonhoeffer, T. & Nagerl, U. V. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245 (2006).

    CAS  PubMed  Google Scholar 

  119. Dong, C., Upadhya, S. C., Ding, L., Smith, T. K. & Hegde, A. N. Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation. Learn. Mem. 15, 335–347 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Bingol, B. et al. Autophosphorylated CaMKIIa acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567–578 (2010).

    CAS  PubMed  Google Scholar 

  121. Sharma, K., Fong, D. K. & Craig, A. M. Postsynaptic protein mobility in dendritic spines: long-term regulation by synaptic NMDA receptor activation. Mol. Cell Neurosci. 31, 702–712 (2006).

    CAS  PubMed  Google Scholar 

  122. Okada, D., Ozawa, F. & Inokuchi, K. Input-specific spine entry of soma-derived Vesl-1s protein conforms to synaptic tagging. Science 324, 904–909 (2009).

    CAS  PubMed  Google Scholar 

  123. Ehlers, M. D. Molecular morphogens for dendritic spines. Trends Neurosci. 25, 64–67 (2002).

    CAS  PubMed  Google Scholar 

  124. Brakeman, P. R. et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284–288 (1997).

    CAS  PubMed  Google Scholar 

  125. Tu, J. C. et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23, 583–592 (1999).

    CAS  PubMed  Google Scholar 

  126. Xiao, B., Tu, J. C. & Worley, P. F. Homer: a link between neural activity and glutamate receptor function. Curr. Opin. Neurobiol. 10, 370–374 (2000).

    CAS  PubMed  Google Scholar 

  127. Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

    CAS  PubMed  Google Scholar 

  128. Pak, D. T., Yang, S., Rudolph-Correia, S., Kim, E. & Sheng, M. Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31, 289–303 (2001).

    CAS  PubMed  Google Scholar 

  129. Komai, S. et al. Neuropsin regulates an early phase of schaffer-collateral long-term potentiation in the murine hippocampus. Eur. J. Neurosci. 12, 1479–1486 (2000).

    CAS  PubMed  Google Scholar 

  130. Matsumoto-Miyai, K. et al. NMDA-dependent proteolysis of presynaptic adhesion molecule L1 in the hippocampus by neuropsin. J. Neurosci. 23, 7727–7736 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ishikawa, Y., Horii, Y., Tamura, H. & Shiosaka, S. Neuropsin (KLK8)-dependent and -independent synaptic tagging in the Schaffer-collateral pathway of mouse hippocampus. J. Neurosci. 28, 843–849 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Nagy, V. et al. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J. Neurosci. 26, 1923–1934 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell 115, 893–904 (2003).

    CAS  PubMed  Google Scholar 

  134. Si, K., Lindquist, S. & Kandel, E. R. A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115, 879–891 (2003).

    CAS  PubMed  Google Scholar 

  135. Tsokas, P. et al. Local protein synthesis mediates a rapid increase in dendritic elongation factor 1a after induction of late long-term potentiation. J. Neurosci. 25, 5833–5843 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Giustetto, M. et al. Axonal transport of eukaryotic translation elongation factor 1α mRNA couples transcription in the nucleus to long-term facilitation at the synapse. Proc. Natl Acad. Sci. USA 100, 13680–13685 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bailey, C. H., Kandel, E. R. & Si, K. The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth. Neuron 44, 49–57 (2004).

    CAS  PubMed  Google Scholar 

  138. Govindarajan, A., Kelleher, R. J. & Tonegawa, S. A clustered plasticity model of long-term memory engrams. Nature Rev. Neurosci. 7, 575–583 (2006).

    CAS  Google Scholar 

  139. Richter, J. D. & Klann, E. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 23, 1–11 (2009).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the UK Medical Research Council, the Volkswagen Stiftung and the Human Frontiers Science Program. We are grateful to many colleagues for discussion of these ideas, including T. Bonhoeffer, R. Fonseca, H. Bito, H. Okuno, M. van Rossum and A. Barrett, and our colleagues in the Laboratory for Cognitive Neuroscience. R.L.R. is now at the Picower Institute, MIT. R.G.M.M. is a Royal Society/Wolfson Professor at the University of Edinburgh. Special thanks to C. Wiedemann for the invitation and encouragement to write this Review.

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Correspondence to Richard G. M. Morris.

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Supplementary information

Supplementary information S1 (movie)

E-LTP: Due to the lack of PRPs, a synapse that has undergone both functional and structural plasticity returns to its basal state. (SWF 26 kb)

Supplementary information S2 (movie)

L-LTP: Following structural and functional plasticity changes, PRPs find a receptive synapse to which they can contribute. (SWF 27 kb)

Supplementary information S3 (figure)

Three challenges to STC explained. (PDF 207 kb)

Supplementary information S4 (movie)

Tag block leads to E-LTP: The inhibition of structural plasticity still allows for the functional expression of E-LTP but this is short-lasting as the available PRPs are not allowed to contribute to the maintenance of L-LTP. (SWF 69 kb)

Supplementary information S5 (movie)

Slow onset plasticity: Even without the immediate expression of LTP, structural plasticity makes the synapse receptive to PRPs allowing LTP to develop gradually. (SWF 22 kb)

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FURTHER INFORMATION

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Glossary

Engram

The concept, first introduced in the nineteenth century, to define the physical entity in the brain that stores information over time and later enables memories to be expressed.

Memory encoding

The physiological process by which patterns of neural activity result in the creation (that is, encoding) of a state somewhere in the brain that can be characterized as an engram.

Two-pathway LTP experiment

An experiment that studies two independent sets of synapses that converge onto the same cell.

Cross-capture experiment

A two-pathway experiment in which a weak, early-long-term potentiation (E-LTP)-inducing protocol delivered to one pathway is rescued into late-LTP (L-LTP) if a strong, L-LTD-inducing protocol is delivered to the other pathway at around the same time. The phenomenon is reciprocal, as rescue of E-LTD into L-LTD occurs when another pathway experiences a strong, L-LTP-inducing protocol.

Place cell

A neuron that exhibits a high rate of firing when an animal is at a specific location in an environment.

PSD slot

A group of proteins in the postsynaptic density (PSD) that is capable of binding AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole) receptors.

Immediate early genes

Genes whose expression is upregulated transiently but quickly in response to a specific stimulus, such as memory encoding.

Competitive maintenance

The theory explaining the observation that two pathways already expressing long-term potentiation (LTP) will compete for scarce plasticity-related products when they are further tetanized after a period of protein synthesis inhibition during the maintenance phases of LTP.

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Redondo, R., Morris, R. Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12, 17–30 (2011). https://doi.org/10.1038/nrn2963

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