Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3–CA1 synapses

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Although the function of the p42/p44 mitogen-activated protein (MAP) kinase pathway in long-term potentiation at hippocampal CA3–CA1 synapses has been well described, relatively little is known about the importance of the p38 MAP kinase pathway in synaptic plasticity. Here we show that the p38 MAP kinase pathway, a parallel signaling cascade activated by distinct upstream kinases, mediates the induction of metabotropic glutamate receptor-dependent long-term depression at CA3–CA1 synapses. Thus, two parallel MAP kinase pathways contribute to opposing forms of long-term plasticity at a central synapse.

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Figure 1: p38 MAPK is present in hippocampus.
Figure 2: Blockade of p38 and p42/44 MAPK pathways have complementary effects on LTD and LTP.
Figure 3: Activated p38 MAPK simulated and occluded LTD.
Figure 4: Activated p38 MAPK increases relative variability of EPSCs consistent with a decrease in transmitter release.
Figure 5: LTD-inducing stimuli enhanced phosphorylation of p38 MAPK but not phosphorylation of p42/44 MAPK (ERK).
Figure 6: Effects of LTD-inducing stimuli and mGluR agents on p38 phosphorylation.


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We thank E. Frank for computer programs and suggestions, A. Moschin and M. Bergamaschi for secretarial assistance, C. Chiamulera and M. Corsi for support and discussions, and E. Odell for help in preparing figures. Supported by Glaxo Wellcome S.p.A. (F.B. and L.C.), the Whitehall Foundation (V.B.), and grants NS-29832 (S.A.S.) and DK-34128 (M.H.C.) from the U.S.P.H.S.

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Correspondence to S. A. Siegelbaum.

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