Abstract
The steroid hormone, estradiol (E(2)), has numerous targets in the central nervous system, including the hippocampus, which plays a key role in cognition and affective behavior. This review focuses on our evidence from studies in rodents that E(2) has diverse mechanisms in the hippocampus for its functional effects. E(2) has rapid, membrane-mediated effects in the hippocampus to enhance cognitive performance. Administration of E(2) to the hippocampus of rats for 10 min following training enhances performance in a hippocampus-mediated task. Increased cell firing in the hippocampus occurs within this short-time frame. Furthermore, administration of free E(2) or an E(2) conjugate, E(2):bovine serum albumin (BSA), to the hippocampus produces similar performance-enhancing effects in this task, suggesting that E(2) has membrane actions in the hippocampus for these effects. Further evidence that E(2) has rapid, membrane-mediated effects is that co-administration of E(2) and inhibitors of mitogen-activated protein kinase (MAPK), rather than intracellular E(2) receptors (ERs) or protein synthesis, attenuate the enhancing effects of E(2) in this task. Despite these data that demonstrate E(2) can have rapid and/or membrane-mediated effects in the hippocampus, there is clear evidence to suggest that intracellular ERs, particularly the beta (rather than alpha) isoform of ERs, may be important targets for E(2)'s functional effects for hippocampal processes. Administration of ligands that are specific for ERbeta, but not ERalpha, have enhancing effects on hippocampal processes similar to that of E(2) (which has similar affinity for ERalpha and ERbeta). These effects are attenuated when ERbeta expression is knocked down in transgenic models or with central administration of antisense oligonucleotides. Thus, there may be a convergence of E(2)'s actions through rapid, membrane-mediated effects and intracellular ERs in the hippocampus for these functional effects.