Skip to main content

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

  • Chapter
  • First Online:
  • 845 Accesses

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.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abel T, Nguyen PV (2008) Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog Brain Res 169:97–115

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Abraham WC (2008) Metaplasticity: tuning synapses and networks for plasticity. Nat Rev Neurosci 9(5):387

    Article  PubMed  CAS  Google Scholar 

  • Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19(4):126–130

    Article  PubMed  CAS  Google Scholar 

  • 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):10924–10929

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):256–264

    Article  PubMed  CAS  Google Scholar 

  • Andersen P, Morris RG, Amaral D, Bliss T, O’Keefe J (2007) The hippocampus book. Oxford University, New York

    Google Scholar 

  • 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):689–703

    Article  PubMed  CAS  Google Scholar 

  • 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):13753–13762

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Besnard A, Caboche J, Laroche S (2012) Reconsolidation of memory: a decade of debate. Prog Neurobiol 99(1):61–80

    Article  PubMed  Google Scholar 

  • 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):331–356

    PubMed  CAS  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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):147–156

    Article  PubMed  CAS  Google Scholar 

  • 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):445–459

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Connor SA, Hoeffer CA, Klann E, Nguyen PV (2011a) Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus. Learn Mem 18(4):207–220

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Connor SA, Wang YT, Nguyen PV (2011b) Activation of beta-adrenergic receptors facilitates heterosynaptic translation-dependent long-term potentiation. J Physiol 589(Pt 17):4321–4340

    PubMed  CAS  PubMed Central  Google Scholar 

  • 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):6566–6570

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):11980–11990

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):747–755

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):493–505

    Article  PubMed  CAS  Google Scholar 

  • Frey U, Morris RG (1997) Synaptic tagging and long-term potentiation. Nature 385(6616):533–536

    Article  PubMed  CAS  Google Scholar 

  • Frey U, Morris RG (1998) Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci 21(5):181–188

    Article  PubMed  CAS  Google Scholar 

  • 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):281–289

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):870–873

    Article  PubMed  CAS  Google Scholar 

  • Govindarajan A, Kelleher RJ, Tonegawa S (2006) A clustered plasticity model of long-term memory engrams. Nat Rev Neurosci 7(7):575–583

    Article  PubMed  CAS  Google Scholar 

  • Hou Q, Gilbert J, Man HY (2011) Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation. Neuron 72(5):806–818

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):635–642

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hulme SR, Jones OD, Abraham WC (2013) Emerging roles of metaplasticity in behaviour and disease. Trends Neurosci 36(6):353–362

    Article  PubMed  CAS  Google Scholar 

  • Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294(5544):1030–1038

    Article  PubMed  CAS  Google Scholar 

  • Kelly MT, Crary JF, Sacktor TC (2007) Regulation of protein kinase Mzeta synthesis by multiple kinases in long-term potentiation. J Neurosci 27(13):3439–3444

    Article  PubMed  CAS  Google Scholar 

  • 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):416–419

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):353–363

    Article  PubMed  Google Scholar 

  • 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):170–177

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Makino H, Malinow R (2009) AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64(3):381–390

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Martin KC, Kosik KS (2002) Synaptic tagging—who’s it? Nat Rev Neurosci 3(10):813–820

    Article  PubMed  CAS  Google Scholar 

  • 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):1678–1683

    Article  PubMed  CAS  Google Scholar 

  • 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):891–904

    Article  PubMed  CAS  Google Scholar 

  • McKay BM, Oh MM, Disterhoft JF (2013) Learning increases intrinsic excitability of hippocampal interneurons. J Neurosci 33(13):5499–5506

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):7476–7481

    Article  PubMed  CAS  Google Scholar 

  • 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):12931–12936

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 2012:687909

    PubMed  PubMed Central  Google Scholar 

  • 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):605–611

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):728–736

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):752–758

    Article  PubMed  CAS  Google Scholar 

  • 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):886–898

    Article  PubMed  CAS  Google Scholar 

  • 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):70–83

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):7843–7851

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):13132–13138

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):8704–8709

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):14437–14442

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Redondo RL, Morris RG (2011) Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12(1):17–30

    Article  PubMed  CAS  Google Scholar 

  • 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):4981–4989

    Article  PubMed  CAS  Google Scholar 

  • Rose J, Jin SX, Craig AM (2009) Heterosynaptic molecular dynamics: locally induced propagating synaptic accumulation of CaM kinase II. Neuron 61(3):351–358

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sacktor TC (2011) How does PKMζ maintain long-term memory? Nat Rev Neurosci 12(1):9–15

    Article  PubMed  CAS  Google Scholar 

  • 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):8342–8346

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sajikumar S, Frey JU (2004) Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD. Neurobiol Learn Mem 82(1):12–25

    Article  PubMed  CAS  Google Scholar 

  • 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):178–186

    Article  PubMed  Google Scholar 

  • 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):2551–2556

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):5068–5080

    Article  PubMed  CAS  Google Scholar 

  • 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):5750–5756

    Article  PubMed  CAS  Google Scholar 

  • 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):9170–9178

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sanhueza M, Lisman J (2013) The CaMKII/NMDAR complex as a molecular memory. Mol Brain 6:10

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211–223

    Article  PubMed  CAS  Google Scholar 

  • Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20(1):11–21

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Serrano P, Yao Y, Sacktor TC (2005) Persistent phosphorylation by protein kinase M zeta maintains late-phase long-term potentiation. J Neurosci 25(8):1979–1984

    Article  PubMed  CAS  Google Scholar 

  • Shema R, Hazvi S, Sacktor TC, Dudai Y (2009) Boundary conditions for the maintenance of memory by PKMzeta in neocortex. Learn Mem 16(2):122–128

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):951–953

    Article  PubMed  CAS  Google Scholar 

  • 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):627–638

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Vitureira N, Letellier M, Goda Y (2012) Homeostatic synaptic plasticity: from single synapses to neural circuits. Curr Opin Neurobiol 22(3):516–521

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):420–423

    Article  PubMed  CAS  Google Scholar 

  • Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313(5790):1093–1097

    Article  PubMed  CAS  Google Scholar 

  • Woo NH, Nguyen PV (2002) “Silent” metaplasticity of the late phase of long-term potentiation requires protein phosphatases. Learn Mem 9(4):202–213

    Article  PubMed  PubMed Central  Google Scholar 

  • Woo NH, Nguyen PV (2003) Protein synthesis is required for synaptic immunity to depotentiation. J Neurosci 23(4):1125–1132

    PubMed  CAS  Google Scholar 

  • 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):7820–7827

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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):1784–1794

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):7221–7231

    Article  PubMed  CAS  Google Scholar 

  • 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):460–468

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter V. Nguyen .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Connor, S.A., Nguyen, P.V. (2015). Prescient Synapses: Gating Future Neuronal Consciousness Through Synaptic Tagging and Metaplasticity. In: Sajikumar, S. (eds) Synaptic Tagging and Capture. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1761-7_11

Download citation

Publish with us

Policies and ethics