{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:03:32Z","timestamp":1780463012323,"version":"3.54.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The alpha-isoform of calcium\/calmodulin-dependent kinase II (\u03b1CaMKII) is a major synaptic kinase that undergoes autophosphorylation after NMDA receptor activation, switching the kinase into a calcium-independent activity state. This \u03b1CaMKII autophosphorylation is essential for NMDA receptor-dependent long-term potentiation (LTP), induced by a single tetanus, in hippocampal area CA1 and in neocortex. Furthermore, the \u03b1CaMKII autophosphorylation is essential for contextual long-term memory (LTM) formation after a single training trial but not after a massed training session. Here, we show that in the absence of \u03b1CaMKII autophosphorylation contextual fear conditioning is hippocampus dependent and that multi-tetanus-dependent late-LTP cannot be induced in hippocampal area CA1. Furthermore, we show that in the absence of \u03b1CaMKII autophosphorylation contextual LTM persists for 30 days, the latest time point tested. Additionally, contextual, but not cued, LTM formation in the absence of \u03b1CaMKII autophosphorylation appears to be impaired in 18 month-old mice. Taken together, our findings suggest that \u03b1CaMKII autophosphorylation-independent plasticity in the hippocampus is sufficient for contextual LTM formation and that \u03b1CaMKII autophosphorylation may be important for delaying age-related impairments in hippocampal memory formation. Furthermore, they propose that NMDA receptor-dependent LTP in hippocampal area CA1 is essential for contextual LTM formation after a single trial but not after massed training. Finally, our results challenge the proposal that NMDA receptor-dependent LTP in neocortex is required for remote contextual LTM.<\/jats:p>","DOI":"10.1186\/1756-6606-4-8","type":"journal-article","created":{"date-parts":[[2011,2,8]],"date-time":"2011-02-08T14:51:14Z","timestamp":1297176674000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Properties of Contextual Memory Formed in the Absence of \u03b1CaMKII Autophosphorylation"],"prefix":"10.1186","volume":"4","author":[{"given":"Elaine E","family":"Irvine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Danhiez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasia","family":"Radwanska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Nassim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Lucchesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile","family":"Godaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Ris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K Peter","family":"Giese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,1,28]]},"reference":[{"key":"108_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/361031a0","volume":"361","author":"TV Bliss","year":"1993","unstructured":"Bliss TV, Collingridge GL: A synaptic model or memory: long-term potentiation in the hippocampus. Nature. 1993, 361: 31-39. 10.1038\/361031a0.","journal-title":"Nature"},{"key":"108_CR2","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1146\/annurev.neuro.23.1.649","volume":"23","author":"SJ Martin","year":"2000","unstructured":"Martin SJ, Grimwood PD, Morris RG: Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci. 2000, 23: 649-711. 10.1146\/annurev.neuro.23.1.649.","journal-title":"Annu Rev Neurosci"},{"key":"108_CR3","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1523\/JNEUROSCI.2834-05.2006","volume":"26","author":"A Gruart","year":"2006","unstructured":"Gruart A, Mu\u00f1oz MD, Delgado-Garc\u00eda JM: Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci. 2006, 26: 1077-1087. 10.1523\/JNEUROSCI.2834-05.2006.","journal-title":"J Neurosci"},{"key":"108_CR4","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1126\/science.1128134","volume":"313","author":"JR Whitlock","year":"2006","unstructured":"Whitlock JR, Heynen AJ, Shuler MG, Bear MF: Learning induces long-term potentiation in the hippocampus. Science. 2006, 313: 1093-1097. 10.1126\/science.1128134.","journal-title":"Science"},{"key":"108_CR5","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nrn753","volume":"3","author":"J Lisman","year":"2002","unstructured":"Lisman J, Schulman H, Cline H: The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002, 3: 175-190. 10.1038\/nrn753.","journal-title":"Nat Rev Neurosci"},{"key":"108_CR6","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1126\/science.279.5352.870","volume":"279","author":"KP Giese","year":"1998","unstructured":"Giese KP, Fedorov NB, Filipkowski RK, Silva AJ: Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 1998, 279: 870-873. 10.1126\/science.279.5352.870.","journal-title":"Science"},{"key":"108_CR7","doi-asserted-by":"crossref","first-page":"4428","DOI":"10.1523\/JNEUROSCI.23-11-04428.2003","volume":"23","author":"N Hardingham","year":"2003","unstructured":"Hardingham N, Glazewski S, Pakhotin P, Mizuno K, Chapman PF, Giese KP, Fox K: Neocortical long-term potentiation and experience-dependent synaptic plasticity require alpha-calcium\/calmodulin-dependent protein kinase II autophosphorylation. J Neurosci. 2003, 23: 4428-4436.","journal-title":"J Neurosci"},{"key":"108_CR8","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/nn985","volume":"6","author":"H Yasuda","year":"2003","unstructured":"Yasuda H, Barth AL, Stellwagen D, Malenka RC: A developmental switch in the signaling cascades for LTP induction. Nat Neurosci. 2003, 6: 15-16. 10.1038\/nn985.","journal-title":"Nat Neurosci"},{"key":"108_CR9","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1113\/jphysiol.2006.111559","volume":"574","author":"SF Cooke","year":"2006","unstructured":"Cooke SF, Wu J, Plattner F, Errington M, Rowan M, Peters M, Hirano A, Bradshaw KD, Anwyl R, Bliss TV, Giese KP: Autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse. J Physiol. 2006, 574: 805-818. 10.1113\/jphysiol.2006.111559.","journal-title":"J Physiol"},{"key":"108_CR10","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/72945","volume":"3","author":"C Rampon","year":"2000","unstructured":"Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, Tsien JZ: Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat Neurosci. 2000, 3: 238-244. 10.1038\/72945.","journal-title":"Nat Neurosci"},{"key":"108_CR11","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.nlm.2007.08.016","volume":"89","author":"MR Hunsaker","year":"2008","unstructured":"Hunsaker MR, Kesner RP: Dissociations across the dorsal-ventral axis of CA3 and CA1 for encoding and retrieval of contextual and auditory-cued fear. Learn Mem. 2008, 89: 61-69. 10.1016\/j.nlm.2007.08.016.","journal-title":"Learn Mem"},{"key":"108_CR12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nn1431","volume":"8","author":"EE Irvine","year":"2005","unstructured":"Irvine EE, Vernon J, Giese KP: AlphaCaMKII autophosphorylation contributes to rapid learning but is not necessary for memory. Nat Neurosci. 2005, 8: 411-412.","journal-title":"Nat Neurosci"},{"key":"108_CR13","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/31371","volume":"393","author":"I Izquierdo","year":"1998","unstructured":"Izquierdo I, Barros DM, Mello e Souza T, de Souza MM, Izquierdo LA, Medina JH: Mechanisms for memory types differ. Nature. 1998, 393: 635-636. 10.1038\/31371.","journal-title":"Nature"},{"key":"108_CR14","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0092-8674(94)90400-6","volume":"79","author":"R Bourtchuladze","year":"1994","unstructured":"Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ: Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994, 79: 59-68. 10.1016\/0092-8674(94)90400-6.","journal-title":"Cell"},{"key":"108_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0960-9822(06)00022-4","volume":"7","author":"JH Kogan","year":"1997","unstructured":"Kogan JH, Frankland PW, Blendy JA, Coblentz J, Marowitz Z, Sch\u00fctz G, Silva AJ: Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol. 1997, 7: 1-11. 10.1016\/S0960-9822(06)00022-4.","journal-title":"Curr Biol"},{"key":"108_CR16","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev.neuro.21.1.127","volume":"21","author":"AJ Silva","year":"1998","unstructured":"Silva AJ, Kogan JH, Frankland PW, Kida S: CREB and memory. Annu Rev Neurosci. 1998, 21: 127-148. 10.1146\/annurev.neuro.21.1.127.","journal-title":"Annu Rev Neurosci"},{"key":"108_CR17","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/1098-1063(2001)11:1<8::AID-HIPO1015>3.0.CO;2-7","volume":"11","author":"SG Anagnostaras","year":"2001","unstructured":"Anagnostaras SG, Gale GD, Fanselow MS: Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus. 2001, 11: 8-17. 10.1002\/1098-1063(2001)11:1<8::AID-HIPO1015>3.0.CO;2-7.","journal-title":"Hippocampus"},{"key":"108_CR18","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1111\/j.1460-9568.2008.06485.x","volume":"28","author":"S Maren","year":"2008","unstructured":"Maren S: Pavlovian fear conditioning as a behavioral assay for hippocampus and amygdala function: cautions and caveats. Eur J Neurosci. 2008, 28: 1661-1666. 10.1111\/j.1460-9568.2008.06485.x.","journal-title":"Eur J Neurosci"},{"key":"108_CR19","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1126\/science.1585183","volume":"256","author":"JJ Kim","year":"1992","unstructured":"Kim JJ, Fanselow MS: Modality-specific retrograde amnesia of fear. Science. 1992, 256: 675-677. 10.1126\/science.1585183.","journal-title":"Science"},{"key":"108_CR20","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/nrn1607","volume":"6","author":"PW Frankland","year":"2005","unstructured":"Frankland PW, Bontempi B: The organization of recent and remote memories. Nat Rev Neurosci. 2005, 6: 119-130. 10.1038\/nrn1607.","journal-title":"Nat Rev Neurosci"},{"key":"108_CR21","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/35077089","volume":"411","author":"PW Frankland","year":"2001","unstructured":"Frankland PW, O'Brien C, Ohno M, Kirkwood A, Silva AJ: Alpha-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature. 2001, 411: 309-313. 10.1038\/35077089.","journal-title":"Nature"},{"key":"108_CR22","doi-asserted-by":"publisher","first-page":"9910","DOI":"10.1523\/JNEUROSCI.2625-08.2008","volume":"28","author":"Fukushima","year":"2008","unstructured":"Fukushima , et al: Upregulation of calcium\/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging. J Neurosci. 2008, 28: 9910-9919. 10.1523\/JNEUROSCI.2625-08.2008. 2008","journal-title":"J Neurosci"},{"key":"108_CR23","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1097\/01.wnr.0000175244.51084.bb","volume":"16","author":"LS von Hertzen","year":"2005","unstructured":"von Hertzen LS, Giese KP: Alpha-isoform of Ca2+\/calmodulin-dependent kinase II autophosphorylation is required for memory consolidation-specific transcription. Neuroreport. 2005, 16: 1411-1414. 10.1097\/01.wnr.0000175244.51084.bb.","journal-title":"Neuroreport"},{"key":"108_CR24","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/85138","volume":"4","author":"MW Jones","year":"2001","unstructured":"Jones MW, Errington ML, French PJ, Fine A, Bliss TV, Garel S, Charnay P, Bozon B, Laroche S, Davis S: A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci. 2001, 4: 289-296. 10.1038\/85138.","journal-title":"Nat Neurosci"},{"key":"108_CR25","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1756-6606-1-6","volume":"1","author":"N Yamasaki","year":"2008","unstructured":"Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T: Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol Brain. 2008, 1: 6-10.1186\/1756-6606-1-6.","journal-title":"Mol Brain"},{"key":"108_CR26","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1016\/j.cell.2009.10.020","volume":"139","author":"T Kitamura","year":"2009","unstructured":"Kitamura T, Saitoh Y, Takashima N, Murayama A, Niibori Y, Ageta H, Sekiguchi M, Sugiyama H, Inokuchi K: Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell. 2009, 139: 814-827. 10.1016\/j.cell.2009.10.020.","journal-title":"Cell"},{"key":"108_CR27","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/nn1847","volume":"10","author":"N Kee","year":"2007","unstructured":"Kee N, Teixeira CM, Wang AH, Frankland PW: Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci. 2007, 10: 355-362. 10.1038\/nn1847.","journal-title":"Nat Neurosci"},{"key":"108_CR28","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1038\/nn1946","volume":"10","author":"MR Hoijati","year":"2007","unstructured":"Hoijati MR, van Woerden GM, Tyler WJ, Giese KP, Silva AJ, Pozzo-Miller L, Elgersma Y: Kinase activity is not required for alphaCaMKII-dependent presynaptic plasticity at CA3-CA1 synapses. Nat Neurosci. 2007, 10: 1125-1127. 10.1038\/nn1946.","journal-title":"Nat Neurosci"},{"key":"108_CR29","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1097\/01.wnr.0000185015.44563.5d","volume":"16","author":"N Amada","year":"2005","unstructured":"Amada N, Aihara K, Ravid R, Horie M: Reduction of NR1 and phosphorylated Ca2+\/calmodulin-dependent protein kinase II levels in Alzheimer's disease. Neuroreport. 2005, 16: 1809-1813. 10.1097\/01.wnr.0000185015.44563.5d.","journal-title":"Neuroreport"},{"key":"108_CR30","doi-asserted-by":"publisher","first-page":"33305","DOI":"10.1074\/jbc.M610390200","volume":"282","author":"M Townsend","year":"2007","unstructured":"Townsend M, Mehta T, Selkoe DJ: Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem. 2007, 282: 33305-33312. 10.1074\/jbc.M610390200.","journal-title":"J Biol Chem"},{"key":"108_CR31","doi-asserted-by":"crossref","first-page":"823","DOI":"10.3233\/JAD-2010-100264","volume":"21","author":"Y Zeng","year":"2010","unstructured":"Zeng Y, Zhao D, Xie CW: Neurotrophins enhance CaMKII activity and rescue amyloid-\u03b2-induced deficits in hippocampal synaptic plasticity. J Alzheimers Dis. 2010, 21: 823-831.","journal-title":"J Alzheimers Dis"},{"key":"108_CR32","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1101\/lm.1.1.34","volume":"1","author":"RG Phillips","year":"1994","unstructured":"Phillips RG, LeDoux JE: Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learn Mem. 1994, 1: 34-44.","journal-title":"Learn Mem"},{"key":"108_CR33","volume-title":"The Mouse Brain in Stereotaxic Coordinates","author":"G Paxinos","year":"2001","unstructured":"Paxinos G, Franklin KJ: The Mouse Brain in Stereotaxic Coordinates. 2001, Academic Press"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1756-6606-4-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T18:16:00Z","timestamp":1637259360000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/1756-6606-4-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1,28]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["108"],"URL":"https:\/\/doi.org\/10.1186\/1756-6606-4-8","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,1,28]]},"assertion":[{"value":"18 October 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 January 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 January 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"8"}}