A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory

Behavioral, biophysical, and pharmacological studies have implicated the hi ppocampus in the formation and storage of spatial memory. However, the mole cular mechanisms underlying long-term spatial memory are poorly understood. In this study, we show that mitogen-activated protein kinase (MAPK, also c alled ERK) is activated in the dorsal, but not the ventral, hippocampus of rats after training in a spatial memory task, the Morris water maze. The ac tivation was expressed as enhanced phosphorylation of MAPK in the pyramidal neurons of the CA1/CA2 subfield. In contrast, no increase in the percentag e of phospho-MAPK-positive cells was detected in either the CA3 subfield or the dentate gyrus. The enhanced phosphorylation was observed only after mu ltiple training trials but not after a single trial or after multiple trial s in which the location of the target platform was randomly changed between each trial. Inhibition of the MAPK/ERK cascade in dorsal hippocampi did no t impair acquisition, but blocked the formation of long-term spatial memory . In contrast, intrahippocampal infusion of SB203580, a specific inhibitor of the stress-activated MAPK (p38 MAPK), did not interfere with memory stor age. These results demonstrate a MAPK-mediated cellular event in the CA1/CA 2 subfields of the dorsal hippocampus that is critical for long-term spatia l memory.