Although important information is available on the molecular mechanisms of long-term memory formation, little is known about the processes underlying memory persistence in the brain. Here, we report that persistent gene expression of CaMKIIδ isoform participates in object recognition long-lasting memory storage in mice hippocampus. We found that CaMKIIδ mRNA expression was sustained up to one week after training and paralleled memory retention. Antisense DNA infusion in the hippocampus during consolidation or even after consolidation impairs 7-day- but not 1-day-long memory, supporting a role of CaMKIIδ in memory persistence. CaMKIIδ gene expression was accompanied by long-lasting nucleosome occupancy changes at its promoter. This epigenetic mechanism is described for the first time in a memory process and offers a novel mechanism for persistent gene expression in neurons. CaMKIIδ protein is mainly present in nucleus and presynaptic terminals, suggesting a role in these subcellular compartments for memory persistence. All these results point to a key function of the sustained gene expression of this overlooked CaMKII isoform in long-lasting memories.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Zovkic IB, Guzman-Karlsson MC, Sweatt JD (2013) Epigenetic regulation of memory formation and maintenance. Learn Mem 20(2):61–74
Miller CA, Gavin CF, White JA, Parrish RR, Honasoge A, Yancey CR, Rivera IM, Rubio MD et al (2010) Cortical DNA methylation maintains remote memory. Nat Neurosci 13(6):664–666
Federman N, de la Fuente V, Zalcman G, Corbi N, Onori A, Passananti C, Romano A (2013) Nuclear factor κB-dependent histone acetylation is specifically involved in persistent forms of memory. J Neurosci 33(17):7603–7614
Kwapis JL, Helmstetter FJ (2014) Does PKM(zeta) maintain memory? Brain Res Bull 105:36–45
Tsokas P, Hsieh C, Yao Y, Lesburguères E, Wallace EJC, Tcherepanov A, Jothianandan D, Hartley BR et al (2016) Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice. eLife 5
Bangaru MLY, Meng J, Kaiser DJ, Yu H, Fischer G, Hogan QH, Hudmon A (2015) Differential expression of CaMKII isoforms and overall kinase activity in rat dorsal root ganglia after injury. Neuroscience 300:116–127
Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3(3):175–190
Lucchesi W, Mizuno K, Giese KP (2011) Novel insights into CaMKII function and regulation during memory formation. Brain Res Bull 85(1–2):2–8
Irvine EE, von Hertzen LSJ, Plattner F, Giese KP (2006) alphaCaMKII autophosphorylation: a fast track to memory. Trends Neurosci 29(8):459–465
Bachstetter AD, Webster SJ, Tu T, Goulding DS, Haiech J, Watterson DM, van Eldik LJ (2014) “Generation and behavior characterization of CaMKIIβ knockout mice,” PLoS One, vol. 9, no. 8.
Sirri A, Bianchi V, Pelizzola M, Mayhaus M, Ricciardi-Castagnoli P, Toniolo D, D'Adamo P (2010) Temporal gene expression profile of the hippocampus following trace fear conditioning. Brain Res 1308:14–23
Jarome TJ, Thomas JS, Lubin FD (2014) The epigenetic basis of memory formation and storage. Prog Mol Biol Transl Sci 128:1–27
Zovkic IB, Paulukaitis BS, Day JJ, Etikala DM, Sweatt JD (2014) Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515(7528):582–586
Maze I, Wenderski W, Noh KM, Bagot RC, Tzavaras N, Purushothaman I, Elsässer SJ, Guo Y et al (2015) Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87(1):77–94
Vogel-Ciernia A, Matheos DP, Barrett RM, Kramár EA, Azzawi S, Chen Y, Magnan CN, Zeller M et al (2013) The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nat Neurosci 16(5):552–561
Vogel-Ciernia A, Wood MA (2014) Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory and intellectual disability disorders. Neuropharmacology 80:18–27
Hemstedt TJ, Lattal KM, Wood MA (2017) Reconsolidation and extinction: using epigenetic signatures to challenge conventional wisdom. Neurobiol Learn Mem 142:55–65
López AJ, Wood MA (2015) Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders. Front Behav Neurosci 9:100
Bai L, Morozov AV (2010) Gene regulation by nucleosome positioning. Trends Genet 26(11):476–483
McGaugh JL (2000) Memory—a century of consolidation. Science 287(5451):248–251
Neidl R, Schneider A, Bousiges O, Majchrzak M, Barbelivien A, de Vasconcelos AP, Dorgans K, Doussau F et al (2016) Late-life environmental enrichment induces acetylation events and nuclear factor κB-dependent regulations in the hippocampus of aged rats showing improved plasticity and learning. J Neurosci 36(15):4351–4361
Ponts N, Harris EY, Lonardi S, Le Roch KG (2011) Nucleosome occupancy at transcription start sites in the human malaria parasite: a hard-wired evolution of virulence? Infect Genet Evol 11(4):716–724
Tirosh I, Barkai N (2008) Two strategies for gene regulation by promoter nucleosomes. Genome Res 18(7):1084–1091
Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61(3):340–350
Morris RGM (2013) NMDA receptors and memory encoding. Neuropharmacology 74:32–40
Shen K, Teruel MN, Subramanian K, Meyer T (1998) CaMKIIbeta functions as an F-actin targeting module that localizes CaMKIIalpha/beta heterooligomers to dendritic spines. Neuron 21(3):593–606
Miller S, Yasuda M, Coats JK, Jones Y, Martone ME, Mayford M (2002) Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36(3):507–519
Mishra S, Gray CBB, Miyamoto S, Bers DM, Brown JH (2011) Location matters: clarifying the concept of nuclear and cytosolic CaMKII subtypes. Circ Res 109(12):1354–1362
Ma H, Li B, Tsien RW (2015) Distinct roles of multiple isoforms of CaMKII in signaling to the nucleus. Biochim Biophys Acta 1853(9):1953–1957
Shema R, Haramati S, Ron S, Hazvi S, Chen A, Sacktor TC, Dudai Y (2011) Enhancement of consolidated long-term memory by overexpression of protein kinase Mζ in the neocortex. Science 331(6021):1207–1210
Hsieh C et al. (2016) Persistent increased PKMζ in long-term and remote spatial memory. Neurobiol Learn Mem
Xiao H-S, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ et al (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A 99(12):8360–8365
Katche C, Bekinschtein P, Slipczuk L, Goldin A, Izquierdo IA, Cammarota M, Medina JH (2010) Delayed wave of c-Fos expression in the dorsal hippocampus involved specifically in persistence of long-term memory storage. Proc Natl Acad Sci U S A 107(1):349–354
Yaida Y, Nowak TS (1995) Distribution of phosphodiester and phosphorothioate oligonucleotides in rat brain after intraventricular and intrahippocampal administration determined by in situ hybridization. Regul Pept 59(2):193–199
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
Quivy V, Van Lint C (2004) Regulation at multiple levels of NF-κB-mediated transactivation by protein acetylation. Biochem Pharmacol 68(6):1221–1229
Kim S, Kaang B-K (2017) Epigenetic regulation and chromatin remodeling in learning and memory. Exp Mol Med 49(1):e281
Lone IN, Shukla MS, Charles Richard JL, Peshev ZY, Dimitrov S, Angelov D (2013) Binding of NF-κB to nucleosomes: effect of translational positioning, nucleosome remodeling and linker histone H1. PLoS Genet 9(9):e1003830
Cohen SJ, Stackman RW (2015) Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav Brain Res 285:105–117
Takeuchi Y, Yamamoto H, Matsumoto K, Kimura T, Katsuragi S, Miyakawa T, Miyamoto E (1999) Nuclear localization of the delta subunit of Ca2+/calmodulin-dependent protein kinase II in rat cerebellar granule cells. J Neurochem 72(2):815–825
Awad S, al-Haffar KMA, Marashly Q, Quijada P, Kunhi M, al-Yacoub N, Wade FS, Mohammed SF et al (2015) Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress. J Pathol 235(4):606–618
Little GH, Bai Y, Williams T, Poizat C (2007) Nuclear calcium/calmodulin-dependent protein kinase IIdelta preferentially transmits signals to histone deacetylase 4 in cardiac cells. J Biol Chem 282(10):7219–7231
Zhang T, Kohlhaas M, Backs J, Mishra S, Phillips W, Dybkova N, Chang S, Ling H et al (2007) CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. J Biol Chem 282(48):35078–35087
Sando R, Gounko N, Pieraut S, Liao L, Yates J, Maximov A (2012) HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151(4):821–834
Wang W-H et al (2011) Intracellular trafficking of histone deacetylase 4 regulates long-term memory formation. Anat Rec 294(6):1025–1034
Fitzsimons HL, Schwartz S, Given FM, Scott MJ (2013) The histone deacetylase HDAC4 regulates long-term memory in Drosophila. PLoS One 8(12):e83903
Ninan I, Arancio O (2004) Presynaptic CaMKII is necessary for synaptic plasticity in cultured hippocampal neurons. Neuron 42(1):129–141
Lu F-M, Hawkins RD (2006) Presynaptic and postsynaptic Ca2+ and CamKII contribute to long-term potentiation at synapses between individual CA3 neurons. Proc Natl Acad Sci U S A 103(11):4264–4269
Paxinos G and Franklin KBJ (2004) The mouse brain in stereotaxic coordinates. Gulf Professional Publishing
Kirk RE (2012) Experimental design: procedures for the behavioral sciences, 4th edn. SAGE Publications, Inc, Thousand Oaks
We thank Dr. María Eugenia Pedreira and Dr. Damian Refojo for helpful comments on the manuscript. This work was supported by research grants from the National Agency of Scientific and Technological Promotion of Argentina (ANPCyT) PICT2369, National Council of Research (CONICET) PIP5466, and University of Buenos Aires grant X198.
Electronic supplementary material
About this article
Cite this article
Zalcman, G., Federman, N., Fiszbein, A. et al. Sustained CaMKII Delta Gene Expression Is Specifically Required for Long-Lasting Memories in Mice. Mol Neurobiol 56, 1437–1450 (2019). https://doi.org/10.1007/s12035-018-1144-3
- Long-term memory
- Nucleosome occupancy