A necessity for MAP kinase activation in mammalian spatial learning

Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of p rotein kinases and phosphorylation of their downstream effectors plays a ma jor role. Recent findings in our laboratory have shown a requirement for th e mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic p lasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to te st the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperiton eally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked. contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatia l learning, we administered. SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platf orm compared with vehicle-treated controls and also failed to use a selecti ve search strategy during subsequent probe mars in which the platform was r emoved. These impairments subsequent probe trials in which the cannot be at tributed to nonspecific effects the drug during the training phase; no defi cit was seen in the visible platform and. injection of SL327 following trai ning produced no effect on the performance of these mice in the hidden plat form task. These findings indicate that the MAPK cascade is required for sp atial and contextual learning in mice.