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The MAPK cascade is required for mammalian associative learning

Abstract

Mitogen-activated protein kinase (MAPK) is an integral component of cellular signaling during mitogenesis and differentiation of mitotic cells. Recently MAPK activation in post-mitotic cells has been implicated in hippocampal long-term potentiation (LTP), a potential cellular mechanism of learning and memory. Here we investigate the involvement of MAPK in learning and memory in behaving animals. MAPK activation increased in the rat hippocampus after an associative learning task, contextual fear conditioning. Two other protein kinases known to be activated during hippocampal LTP, protein kinase C and α-calcium/calmodulin protein kinase II, also were activated in the hippocampus after learning. Inhibition of the specific upstream activator of MAPK, MAPK kinase (MEK), blocked fear conditioning. Thus, classical conditioning in mammals activates MAPK, which is necessary for consolidation of the resultant learning.

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Figure 1: Fear conditioning results in associative learning and MAPK activation.
Figure 2: Autophosphorylation of PKC and α-CaMKII increases during fear conditioning.
Figure 3: MK801 attenuates the increase in activated MAPK during fear conditioning.
Figure 4: A specific inhibitor of MEK blocks fear conditioning.
Figure 5: SL327 inhibits MAPK activation and LTP in the hippocampus.

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Acknowledgements

We thank A. Newton for providing a PKC antibody. We thank J.P. Adams, A.E. Anderson, C.M. Kondratick, H.-C. Lu, A.A. Oliva, R. Paylor and S.R. Sinha for reading the manuscript, P.K. Dash for discussions, and R. Paylor for technical assistance. This work was supported by the National Institutes of Health (J.D.S., MH 57014) and a Williams Stamps Farish graduate fellowship (C.M.A.).

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Correspondence to J. David Sweatt.

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Atkins, C., Selcher, J., Petraitis, J. et al. The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1, 602–609 (1998). https://doi.org/10.1038/2836

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