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Prescient Synapses: Gating Future Neuronal Consciousness Through Synaptic Tagging and Metaplasticity

  • Steven A. Connor
  • Peter V. NguyenEmail author
Chapter

Abstract

Restriction of synaptic plasticity to time frames dictated by fast synaptic transmission would yield neuronal networks incapable of encoding qualitatively rich memories. The ability to associate and encode temporally disparate aspects of a memory confers significant survival advantages. The temporal spread of everyday experiences necessitates broad time windows for synaptic encoding of multiple related events. By extending the time frame in which events can be associated at a synaptic level, and biasing synapses towards a plasticity-conducive state, synaptic tagging and metaplasticity provide potent mechanisms for enhancing memory quality in the brain. Tagging and metaplasticity serve as gateways for augmenting neuronal consciousness. Priming of future synaptic plasticity can enhance neuronal detection, encoding, and association of salient future events, and it can facilitate storage of detailed memories. We review key intracellular signalling mechanisms that initiate lasting changes in the ability of synapses to undergo metaplasticity, along with leading candidate synaptic tags that facilitate metaplasticity. We also speculate on how these phenomena bolster neuronal consciousness to sculpt the brain’s capacity to dynamically encode and store information.

Keywords

Synaptic tagging Metaplasticity Protein kinases and phosphatases Memory Cellular consciousness 

References

  1. Abel T, Nguyen PV (2008) Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog Brain Res 169:97–115PubMedCrossRefPubMedCentralGoogle Scholar
  2. Abraham WC (2008) Metaplasticity: tuning synapses and networks for plasticity. Nat Rev Neurosci 9(5):387PubMedCrossRefGoogle Scholar
  3. Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19(4):126–130PubMedCrossRefGoogle Scholar
  4. Abraham WC, Mason-Parker SE, Bear MF, Webb S, Tate WP (2001) Heterosynaptic metaplasticity in the hippocampus in vivo: a BCM-like modifiable threshold for LTP. Proc Natl Acad Sci U S A 98(19):10924–10929PubMedCrossRefPubMedCentralGoogle Scholar
  5. Alarcon JM, Barco A, Kandel ER (2006) Capture of the late phase of long-term potentiation within and across the apical and basilar dendritic compartments of CA1 pyramidal neurons: synaptic tagging is compartment restricted. J Neurosci 26(1):256–264PubMedCrossRefGoogle Scholar
  6. Andersen P, Morris RG, Amaral D, Bliss T, O’Keefe J (2007) The hippocampus book. Oxford University, New YorkGoogle Scholar
  7. Barco A, Alarcon JM, Kandel ER (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108(5):689–703PubMedCrossRefGoogle Scholar
  8. Barry JM, Rivard B, Fox SE, Fenton AA, Sacktor TC, Muller RU (2012) Inhibition of protein kinase Mζ disrupts the stable spatial discharge of hippocampal place cells in a familiar environment. J Neurosci 32(40):13753–13762PubMedCrossRefPubMedCentralGoogle Scholar
  9. Besnard A, Caboche J, Laroche S (2012) Reconsolidation of memory: a decade of debate. Prog Neurobiol 99(1):61–80PubMedCrossRefGoogle Scholar
  10. Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232(2):331–356PubMedPubMedCentralGoogle Scholar
  11. Cassini LF, Sierra RO, Haubrich J, Crestani AP, Santana F, de Oliveira AL, Quillfeldt JA (2013) Memory reconsolidation allows the consolidation of a concomitant weak learning through a synaptic tagging and capture mechanism. Hippocampus 23(10):931–941. doi: 10.1002/hipo.22149 PubMedCrossRefGoogle Scholar
  12. Chain DG, Casadio A, Schacher S, Hegde AN, Valbrun M, Yamamoto N, Goldberg AL, Bartsch D, Kandel ER, Schwartz JH (1999) Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22(1):147–156PubMedCrossRefGoogle Scholar
  13. Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52(3):445–459PubMedCrossRefPubMedCentralGoogle Scholar
  14. Connor SA, Hoeffer CA, Klann E, Nguyen PV (2011a) Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus. Learn Mem 18(4):207–220PubMedCrossRefPubMedCentralGoogle Scholar
  15. Connor SA, Wang YT, Nguyen PV (2011b) Activation of beta-adrenergic receptors facilitates heterosynaptic translation-dependent long-term potentiation. J Physiol 589(Pt 17):4321–4340PubMedPubMedCentralGoogle Scholar
  16. Da Silva WC, Cardoso G, Bonini JS, Benetti F, Izquierdo I (2013) Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus. Proc Natl Acad Sci U S A 110(16):6566–6570PubMedCrossRefPubMedCentralGoogle Scholar
  17. Dong Z, Gong B, Li H, Bai Y, Wu X, Huang Y, He W, Li T, Wang YT (2012) Mechanisms of hippocampal long-term depression are required for memory enhancement by novelty exploration. J Neurosci 32(35):11980–11990PubMedCrossRefPubMedCentralGoogle Scholar
  18. Duvarci S, Nader K, LeDoux JE (2008) De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala. Learn Mem 15(10):747–755PubMedCrossRefPubMedCentralGoogle Scholar
  19. Elgersma Y, Fedorov NB, Ikonen S, Choi ES, Elgersma M, Carvalho OM, Giese KP, Silva AJ (2002) Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity, and learning. Neuron 36(3):493–505PubMedCrossRefGoogle Scholar
  20. Frey U, Morris RG (1997) Synaptic tagging and long-term potentiation. Nature 385(6616):533–536PubMedCrossRefGoogle Scholar
  21. Frey U, Morris RG (1998) Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci 21(5):181–188PubMedCrossRefGoogle Scholar
  22. Gelinas JN, Tenorio G, Lemon N, Abel T, Nguyen PV (2008) Beta-adrenergic receptor activation during distinct patterns of stimulation critically modulates the PKA-dependence of LTP in the mouse hippocampus. Learn Mem 15(5):281–289PubMedCrossRefPubMedCentralGoogle Scholar
  23. Giese KP, Fedorov NB, Filipkowski RK, Silva AJ (1998) Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279(5352):870–873PubMedCrossRefGoogle Scholar
  24. Govindarajan A, Kelleher RJ, Tonegawa S (2006) A clustered plasticity model of long-term memory engrams. Nat Rev Neurosci 7(7):575–583PubMedCrossRefGoogle Scholar
  25. Hou Q, Gilbert J, Man HY (2011) Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation. Neuron 72(5):806–818PubMedCrossRefPubMedCentralGoogle Scholar
  26. Huang T, McDonough CB, Abel T (2006) Compartmentalized PKA signaling events are required for synaptic tagging and capture during hippocampal late-phase long-term potentiation. Eur J Cell Biol 85(7):635–642PubMedCrossRefPubMedCentralGoogle Scholar
  27. Hulme SR, Jones OD, Abraham WC (2013) Emerging roles of metaplasticity in behaviour and disease. Trends Neurosci 36(6):353–362PubMedCrossRefGoogle Scholar
  28. Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294(5544):1030–1038PubMedCrossRefGoogle Scholar
  29. Kelly MT, Crary JF, Sacktor TC (2007) Regulation of protein kinase Mzeta synthesis by multiple kinases in long-term potentiation. J Neurosci 27(13):3439–3444PubMedCrossRefGoogle Scholar
  30. Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, McMahon T, Dadgar J, Fischbach-Weiss SC (2013) Messing RO (2013) Prkcz null mice show normal learning and memory. Nature 493(7432):416–419PubMedCrossRefPubMedCentralGoogle Scholar
  31. Li Q, Rothkegel M, Xiao ZC, Abraham WC, Korte M, Sajikumar S (2012) Making synapses strong: metaplasticity prolongs associativity of long-term memory by switching synaptic tag mechanisms. Cereb Cortex 24(2):353–363PubMedCrossRefGoogle Scholar
  32. Lin MT, Luján R, Watanabe M, Adelman JP, Maylie J (2008) SK2 channel plasticity contributes to LTP at Schaffer collateral-CA1 synapses. Nat Neurosci 11(2):170–177PubMedCrossRefPubMedCentralGoogle Scholar
  33. Makino H, Malinow R (2009) AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64(3):381–390PubMedCrossRefPubMedCentralGoogle Scholar
  34. Martin KC, Kosik KS (2002) Synaptic tagging—who’s it? Nat Rev Neurosci 3(10):813–820PubMedCrossRefGoogle Scholar
  35. Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER (1996) Control of memory formation through regulated expression of a CaMKII transgene. Science 274(5293):1678–1683PubMedCrossRefGoogle Scholar
  36. Mayford M, Wang J, Kandel ER, O’Dell TJ (1995) CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell 81(6):891–904PubMedCrossRefGoogle Scholar
  37. McKay BM, Oh MM, Disterhoft JF (2013) Learning increases intrinsic excitability of hippocampal interneurons. J Neurosci 33(13):5499–5506PubMedCrossRefPubMedCentralGoogle Scholar
  38. Moncada D, Viola H (2007) Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging. J Neurosci 27(28):7476–7481PubMedCrossRefGoogle Scholar
  39. Moncada D, Ballarini F, Martinez MC, Frey JU, Viola H (2011) Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation. Proc Natl Acad Sci U S A 108(31):12931–12936PubMedCrossRefPubMedCentralGoogle Scholar
  40. Nardone R, Bergmann J, Christova M, Caleri F, Tezzon F, Ladurner G, Trinka E, Golaszewski S (2012) Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review. Int J Alzheimers Dis 2012:687909PubMedPubMedCentralGoogle Scholar
  41. Navakkode S, Sajikumar S, Sacktor TC, Frey JU (2010) Protein kinase Mzeta is essential for the induction and maintenance of dopamine-induced long-term potentiation in apical CA1 dendrites. Learn Mem 17(12):605–611PubMedCrossRefPubMedCentralGoogle Scholar
  42. O’Dell TJ, Connor SA, Gelinas JN, Nguyen PV (2010) Viagra for your synapses: enhancement of hippocampal long-term potentiation by activation of beta-adrenergic receptors. Cell Signal 22(5):728–736PubMedCrossRefPubMedCentralGoogle Scholar
  43. Oh MC, Derkach VA, Guire ES, Soderling TR (2006) Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem 281(2):752–758PubMedCrossRefGoogle Scholar
  44. Okuno H, Akashi K, Ishii Y, Yagishita-Kyo N, Suzuki K, Nonaka M, Kawashima T, Fujii H, Takemoto-Kimura S, Abe M, Natsume R, Chowdhury S, Sakimura K, Worley PF, Bito H (2012) Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ. Cell 149(4):886–898PubMedCrossRefGoogle Scholar
  45. Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF (2008) Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59(1):70–83PubMedCrossRefPubMedCentralGoogle Scholar
  46. Parsons RG, Davis M (2012) A metaplasticity-like mechanism supports the selection of fear memories: role of protein kinase a in the amygdala. J Neurosci 32(23):7843–7851PubMedCrossRefPubMedCentralGoogle Scholar
  47. Pi HJ, Lisman JE (2008) Coupled phosphatase and kinase switches produce the tristability required for long-term potentiation and long-term depression. J Neurosci 28(49):13132–13138PubMedCrossRefPubMedCentralGoogle Scholar
  48. Pi HJ, Otmakhov N, Lemelin D, De Koninck P, Lisman J (2010a) Autonomous CaMKII can promote either long-term potentiation or long-term depression, depending on the state of T305/T306 phosphorylation. J Neurosci 30(26):8704–8709PubMedCrossRefPubMedCentralGoogle Scholar
  49. Pi HJ, Otmakhov N, El Gaamouch F, Lemelin D, De Koninck P, Lisman J (2010b) CaMKII control of spine size and synaptic strength: role of phosphorylation states and nonenzymatic action. Proc Natl Acad Sci U S A 107(32):14437–14442PubMedCrossRefPubMedCentralGoogle Scholar
  50. Redondo RL, Morris RG (2011) Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12(1):17–30PubMedCrossRefGoogle Scholar
  51. Redondo RL, Okuno H, Spooner PA, Frenguelli BG, Bito H, Morris RG (2010) Synaptic tagging and capture: differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation. J Neurosci 30(14):4981–4989PubMedCrossRefGoogle Scholar
  52. Rose J, Jin SX, Craig AM (2009) Heterosynaptic molecular dynamics: locally induced propagating synaptic accumulation of CaM kinase II. Neuron 61(3):351–358PubMedCrossRefPubMedCentralGoogle Scholar
  53. Sacktor TC (2011) How does PKMζ maintain long-term memory? Nat Rev Neurosci 12(1):9–15PubMedCrossRefGoogle Scholar
  54. Sacktor TC, Osten P, Valsamis H, Jiang X, Naik MU, Sublette E (1993) Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation. Proc Natl Acad Sci U S A 90(18):8342–8346PubMedCrossRefPubMedCentralGoogle Scholar
  55. Sajikumar S, Frey JU (2004) Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD. Neurobiol Learn Mem 82(1):12–25PubMedCrossRefGoogle Scholar
  56. Sajikumar S, Li Q, Abraham WC, Xiao ZC (2009) Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1. Learn Mem 16(3):178–186PubMedCrossRefGoogle Scholar
  57. Sajikumar S, Korte M (2011) Metaplasticity governs compartmentalization of synaptic tagging and capture through brain-derived neurotrophic factor (BDNF) and protein kinase Mzeta (PKMzeta). Proc Natl Acad Sci U S A 108(6):2551–2556PubMedCrossRefPubMedCentralGoogle Scholar
  58. Sajikumar S, Navakkode S, Frey JU (2007) 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(19):5068–5080PubMedCrossRefGoogle Scholar
  59. Sajikumar S, Navakkode S, Sacktor TC, Frey JU (2005) Synaptic tagging and cross-tagging: the role of protein kinase Mzeta in maintaining long-term potentiation but not long-term depression. J Neurosci 25(24):5750–5756PubMedCrossRefGoogle Scholar
  60. Sanhueza M, Fernandez-Villalobos G, Stein IS, Kasumova G, Zhang P, Bayer KU, Otmakhov N, Hell JW, Lisman J (2011) Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J Neurosci 31(25):9170–9178PubMedCrossRefPubMedCentralGoogle Scholar
  61. Sanhueza M, Lisman J (2013) The CaMKII/NMDAR complex as a molecular memory. Mol Brain 6:10PubMedCrossRefPubMedCentralGoogle Scholar
  62. Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211–223PubMedCrossRefGoogle Scholar
  63. Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20(1):11–21PubMedCrossRefPubMedCentralGoogle Scholar
  64. Serrano P, Yao Y, Sacktor TC (2005) Persistent phosphorylation by protein kinase M zeta maintains late-phase long-term potentiation. J Neurosci 25(8):1979–1984PubMedCrossRefGoogle Scholar
  65. Shema R, Hazvi S, Sacktor TC, Dudai Y (2009) Boundary conditions for the maintenance of memory by PKMzeta in neocortex. Learn Mem 16(2):122–128PubMedCrossRefPubMedCentralGoogle Scholar
  66. Shema R, Sacktor TC, Dudai Y (2007) Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta. Science 317(5840):951–953PubMedCrossRefGoogle Scholar
  67. Tenorio G, Connor SA, Guévremont D, Abraham WC, Williams J, O’Dell TJ, Nguyen PV (2010) ‘Silent’ priming of translation-dependent LTP by ß-adrenergic receptors involves phosphorylation and recruitment of AMPA receptors. Learn Mem 17(12):627–638PubMedCrossRefPubMedCentralGoogle Scholar
  68. Vitureira N, Letellier M, Goda Y (2012) Homeostatic synaptic plasticity: from single synapses to neural circuits. Curr Opin Neurobiol 22(3):516–521PubMedCrossRefPubMedCentralGoogle Scholar
  69. Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL (2013) PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature 493(7432):420–423PubMedCrossRefGoogle Scholar
  70. Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313(5790):1093–1097PubMedCrossRefGoogle Scholar
  71. Woo NH, Nguyen PV (2002) “Silent” metaplasticity of the late phase of long-term potentiation requires protein phosphatases. Learn Mem 9(4):202–213PubMedCrossRefPubMedCentralGoogle Scholar
  72. Woo NH, Nguyen PV (2003) Protein synthesis is required for synaptic immunity to depotentiation. J Neurosci 23(4):1125–1132PubMedGoogle Scholar
  73. Yao Y, Kelly MT, Sajikumar S, Serrano P, Tian D, Bergold PJ, Frey JU, Sacktor TC (2008) PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J Neurosci 28(31):7820–7827PubMedCrossRefPubMedCentralGoogle Scholar
  74. Young JZ, Isiegas C, Abel T, Nguyen PV (2006) Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging. Eur J Neurosci 23(7):1784–1794PubMedCrossRefPubMedCentralGoogle Scholar
  75. Young JZ, Nguyen PV (2005) Homosynaptic and heterosynaptic inhibition of synaptic tagging and capture of long-term potentiation by previous synaptic activity. J Neurosci 25(31):7221–7231PubMedCrossRefGoogle Scholar
  76. Zelcer I, Cohen H, Richter-Levin G, Lebiosn T, Grossberger T, Barkai E (2006) A cellular correlate of learning-induced metaplasticity in the hippocampus. Cereb Cortex 16(4):460–468PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Centre for NeuroscienceUniversity of Alberta School of MedicineEdmontonCanada
  2. 2.Department of PhysiologyUniversity of Alberta School of MedicineEdmontonCanada
  3. 3.Department of PsychiatryUniversity of Alberta School of MedicineEdmontonCanada

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