Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence

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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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Figure 1: MAPK activity in the hippocampus shows circadian oscillations.
Figure 2: Oscillations in the MAPK pathway occur upstream of MAPK and show oscillations that are free running.
Figure 3: Contextual fear memory formation is dependent on zeitgeber time.
Figure 4: Contextual fear memory is impaired when mice are trained during the subjective night.
Figure 5: cAMP in the hippocampus is higher during the day than at night.
Figure 6: DKO mice do not have diurnal oscillations in pErk activity or cAMP in the hippocampus and are deficient in long-term contextual memory.
Figure 7: Ca2+-stimulated adenylyl cyclase activity and Ras activity in the hippocampus peak during the day.
Figure 8: Infusion of MEK inhibitors into the hippocampus during the circadian peak, but not during the trough of MAPK activation impairs LTM.


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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).

Author information

K.L.E.-M. designed and carried out the experiments and wrote the manuscript. T.P. performed cannulations and assisted with all infusion experiments as well as readings of the manuscript. S.H. carried out experiments using DKO mice, and H.W. contributed to some of the wild-type circadian experiments. G.C.-K.C. provided instruction for the cyclase assays, and both G.C.-K.C. and Z.S.S. contributed to thorough critiques and revisions of the written manuscript. The principal investigator, D.R.S., allowed the research to be conducted in his laboratory and also helped fund the personnel and experiments necessary for the project.

Correspondence to Daniel R Storm.

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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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