To investigate if estrogen modulates long-term potentiation (LTP) via mitogen-activated protein kinase (MAPK) activation, in vitro hippocampal slices were used to induce LTP through extracellular field recordings. Slices perfused with 17beta-estradiol exhibited a significant enhancement of LTP (224+/-19%) compared with LTP in control slices (157+/-9%). In the presence of PD098059, 17beta-estradiol still produced a significant magnitude of LTP (131+/-7%), revealing the existence of p-MAPK-independent LTP mediated by 17beta-estradiol. Immunocytochemistry showed that 17beta-estradiol promoted a transient increase in nuclear translocation of p-MAPK. 17beta-estradiol induced the extracellular proteolysis of neural cell adhesion molecule in a p-MAPK-independent manner, indicating that 17beta-estradiol may act on synaptic remodeling. These results indicate that 17beta-estradiol might affect hippocampal synaptic plasticity in a way involving two separate pathways, which are MAPK-dependent and MAPK-independent.