The mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) signal transduction pathways have critical roles in the consolidation of hippocampus-dependent memory. We found that extracellular regulated kinase 1/2 MAPK phosphorylation and cAMP underwent a circadian oscillation in the hippocampus that was paralleled by changes in Ras activity and the phosphorylation of MAPK kinase and cAMP response element–binding protein (CREB). The nadir of this activation cycle corresponded with severe deficits in hippocampus-dependent fear conditioning under both light-dark and free-running conditions. Circadian oscillations in cAMP and MAPK activity were absent in memory-deficient transgenic mice that lacked Ca2+-stimulated adenylyl cyclases. Furthermore, physiological and pharmacological interference with oscillations in MAPK phosphorylation after the cellular memory consolidation period impaired the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend on reactivation of the cAMP/MAPK/CREB transcriptional pathway in the hippocampus during the circadian cycle.
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We thank H. de la Iglesia for valuable advice concerning some of the circadian procedures. We also would like to thank several members of the Storm lab for insightful discussions and critical readings of this manuscript. This work was supported by a grant from the US National Institutes of Health (NS 20498), a predoctoral Ruth L. Kirschstein US National Institutes of Health Research Award (1 F31 MH075489-01A1) to K.L.E.-M. and a Korea Research Foundation Grant for Young Scientists to S.H. (KRF-2005-213-C00036).
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Eckel-Mahan, K., Phan, T., Han, S. et al. Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence. Nat Neurosci 11, 1074–1082 (2008) doi:10.1038/nn.2174
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