In area CA1 of hippocampal slices which are allowed to recover from slicing "in interface" and where recordings are carried out in interface, a single 1-sec train of 100-Hz stimulation triggers a short-lasting long-term potentiation (S-LTP), which lasts 1-2 h, whereas multiple 1-sec trains induce a long-lasting LTP (L-LTP), which lasts several hours. Moreover, the threshold and the features of these LTP depend on the history of the neurons, a phenomenon known as metaplasticity. Here, where all recordings were performed in interface, we found that allowing the slices to recover "in submersion" had dramatic metaplastic effects. In these conditions, a single 1-sec train at 100 Hz induced an L-LTP which lasted at least 4 h and was dependent on protein synthesis. Interestingly, this type of metaplasticity was observed when the concentration of Mg[superscript plus plus] used was 1.0 mM but not when it was 1.3 mM. The LTP induced by four 1-sec trains at 100 Hz was similar whatever the incubation method. However, the signaling cascades recruited to achieve that pattern were different. In the interface-interface paradigm (recovery and recording both in interface) the four-train induced LTP recruited the PKA signaling pathway but not that of the p42/44MAPK. On the contrary, in the submersion-interface paradigm the four-train induced LTP recruited the p42/44MAPK signaling pathway but not that of the PKA. To our knowledge this is the first example of metaplasticity involving the recruitment of signaling cascades in LTP. (Contains 6 figures.)