An Alternative Mechanism for Long-Term Memory Formation

  • Kasia RadwanskaEmail author
  • Karl Peter Giese


Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses as well as other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Using alpha-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired contextual LTM formation is linked with training-induced PSD95 upregulation followed by persistent generation of multiinnervated spines (MIS), a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. In the chapter, the molecular processes involved in generation of MIS and properties of MIS-dependent memory will be discussed.


αCaMKII autophosphorylation Multiinnervated spines PSD-95 Fear memory Hippocampus 


  1. Belelovsky K, Kaphzan H, Elkobi A, Rosenblum K (2009) Biphasic activation of the mTOR pathway in the gustatory cortex is correlated with and necessary for taste learning. J Neurosci 29:7424–7431CrossRefPubMedGoogle Scholar
  2. Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M (2010) Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140:567–578CrossRefPubMedGoogle Scholar
  3. Cooke SF, Wu J, Plattner F, Errington M, Rowan M, Peters M, Hirano A, Bradshaw KD, Anwyl R, Bliss TV, Giese KP (2006) Autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse. J Physiol 574:805–818CrossRefPubMedCentralPubMedGoogle Scholar
  4. Coultrap SJ, Freund RK, O’Leary H, Sanderson JL, Roche KW, Dell’Acqua ML, Bayer KU (2014) Autonomous CaMKII mediates both LTP and LTD using a mechanism for differential substrate site selection. Cell Rep 6:431–437CrossRefPubMedCentralPubMedGoogle Scholar
  5. Fiala JC, Feinberg M, Popov V, Harris KM (1998) Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci 18:8900–8911PubMedGoogle Scholar
  6. Geinisman Y, Berry RW, Disterhoft JF, Power JM, Van der Zee EA (2001) Associative learning elicits the formation of multiple-synapse boutons. J Neurosci 21:5568–5573PubMedGoogle Scholar
  7. Giese KP, Fedorov NB, Filipkowski RK, Silva AJ (1998) Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279:870–873CrossRefPubMedGoogle Scholar
  8. Giese, KP (2012) Long-term potentiation and memory. In: Memory Mechanisms in Health and Disease, KP Giese, ed., World Scientific, Singapore 1–17Google Scholar
  9. Govindarajan A, Kelleher RJ, Tonegawa S (2006) A clustered plasticity model of long-term memory engrams. Nat Rev Neurosci 7:575–583CrossRefPubMedGoogle Scholar
  10. Gruart A, Munoz MD, Delgado-Garcia JM (2006) Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci 26:1077–1087CrossRefPubMedGoogle Scholar
  11. Hunsaker MR, Lee B, Kesner RP (2008) Evaluating the temporal context of episodic memory: the role of CA3 and CA1. Behav Brain Res 188:310–315CrossRefPubMedGoogle Scholar
  12. Irvine EE, Vernon J, Giese KP (2005) AlphaCaMKII autophosphorylation contributes to rapid learning but is not necessary for memory. Nat Neurosci 8:411–412PubMedGoogle Scholar
  13. Irvine EE, Danhiez A, Radwanska K, Nassim C, Lucchesi W, Godaux E, Ris L, Giese KP (2011) Properties of contextual memory formed in the absence of alphaCaMKII autophosphorylation. Mol Brain 4:8CrossRefPubMedCentralPubMedGoogle Scholar
  14. Kelleher RJ 3rd, Govindarajan A, Tonegawa S (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44:59–73CrossRefPubMedGoogle Scholar
  15. Koob GF (2009) Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology 56(Suppl 1):18–31CrossRefPubMedGoogle Scholar
  16. Lee CC, Huang CC, Wu MY, Hsu KS (2005) Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 280:18543–18550CrossRefPubMedGoogle Scholar
  17. Lee SH, Choi JH, Lee N, Lee HR, Kim JI, Yu NK, Choi SL, Lee SH, Kim H, Kaang BK (2008) Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319:1253–1256CrossRefPubMedGoogle Scholar
  18. Leuner B, Falduto J, Shors TJ (2003) Associative memory formation increases the observation of dendritic spines in the hippocampus. J Neurosci 23:659–665PubMedCentralPubMedGoogle Scholar
  19. Migues PV, Hardt O, Wu DC, Gamache K, Sacktor TC, Wang YT, Nader K (2010) PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat Neurosci 13:630–634CrossRefPubMedGoogle Scholar
  20. Murphy GG, Fedorov NB, Giese KP, Ohno M, Friedman E, Chen R, Silva AJ (2004) Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice. Curr Biol 14:1907–1915CrossRefPubMedGoogle Scholar
  21. Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726CrossRefPubMedGoogle Scholar
  22. Nikonenko I, Jourdain P, Muller D (2003) Presynaptic remodeling contributes to activity-dependent synaptogenesis. J Neurosci 23:8498–8505PubMedGoogle Scholar
  23. Nikonenko I, Boda B, Steen S, Knott G, Welker E, Muller D (2008) PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling. J Cell Biol 183:1115–1127CrossRefPubMedCentralPubMedGoogle Scholar
  24. Petrak LJ, Harris KM, Kirov SA (2005) Synaptogenesis on mature hippocampal dendrites occurs via filopodia and immature spines during blocked synaptic transmission. J Comp Neurol 484:183–190CrossRefPubMedGoogle Scholar
  25. Popov VI, Deev AA, Klimenko OA, Kraev IV, Kuźminykh SB, Medvedev NI, Patrushev IV, Popov RV, Rogachevskii VV, Khutsiyan SS, Stewart MG, Fesenko EE (2005) Three-dimensional reconstruction of synapses and dendritic spines in the rat and ground squirrel hippocampus: new structural-functional paradigms for synaptic function. Neurosci Behav Physiol 35:333–341CrossRefPubMedGoogle Scholar
  26. Radwanska K, Medvedev NI, Pereira GS, Engmann O, Thiede N, Moraes MF, Villers A, Irvine EE, Maunganidze NS, Pyza EM, Ris L, Szymanska M, Lipinski M, Kaczmarek L, Stewart MG, Giese KP (2011) Mechanism for long-term memory formation when synaptic strengthening is impaired. Proc Natl Acad Sci U S A 108:18471–18475CrossRefPubMedCentralPubMedGoogle Scholar
  27. Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, Tsien JZ (2000) Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat Neurosci 3:238–244CrossRefPubMedGoogle Scholar
  28. Restivo L, Vetere G, Bontempi B, Ammassari-Teule M (2009) The formation of recent and remote memory is associated with time-dependent formation of dendritic spines in the hippocampus and anterior cingulate cortex. J Neurosci 29:8206–8214CrossRefPubMedGoogle Scholar
  29. Sacktor TC (2011) How does PKMzeta maintain long-term memory? Nat Rev Neurosci 12:9–15CrossRefPubMedGoogle Scholar
  30. Silva AJ (2003) Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J Neurobiol 54:224–237CrossRefPubMedGoogle Scholar
  31. Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12:585–601CrossRefPubMedCentralPubMedGoogle Scholar
  32. Swiech L, Perycz M, Malik A, Jaworski J (2008) Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta 1784:116–132CrossRefPubMedGoogle Scholar
  33. Toni N, Buchs PA, Nikonenko I, Bron CR, Muller D (1999) LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402:421–425CrossRefPubMedGoogle Scholar
  34. Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093–1097CrossRefPubMedGoogle Scholar
  35. Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA, Tennant K, Jones T, Zuo Y (2009) Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462:915–919CrossRefPubMedCentralPubMedGoogle Scholar
  36. Yang G, Pan F, Gan WB (2009) Stably maintained dendritic spines are associated with lifelong memories. Nature 462:920–924CrossRefPubMedCentralPubMedGoogle Scholar
  37. Yasuda H, Barth AL, Stellwagen D, Malenka RC (2003) A developmental switch in the signaling cascades for LTP induction. Nat Neurosci 6:15–16CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Molecular and Cellular NeuroscienceNencki Institute of Experimental BiologyWarsawPoland
  2. 2.Centre for the Cellular Basis of BehaviourInstitute of Psychiatry, King’s College LondonLondonUK

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