Estrogen regulates the synaptic plasticity and physiology of the hippocampus as well as learning behaviors that are mediated by the hippocampus. The density of dendritic spines and synapses, the number of N-methyl-D-aspartate (NMDA) binding sites, the levels of NMDA receptor subunit NR1 protein, muscimol binding to the gamma-amino butyric acid (GABA)A receptor, and levels of glutamic acid decarboxylase message in the CA1 region of the hippocampus are altered with estrogen treatment. In addition, some of these parameters exhibit sex differences in their response to estrogen treatment. To establish that estrogen can have a direct effect on the hippocampus and to determine whether or not sex differences in estrogen responsiveness are due to sex differences in estrogen receptor (ER) levels, we used immunocytochemistry with the AS409 antibody to map the location of ER-immunoreactive (ER-ir) cells in the hippocampus of male and female rats. We found that (1) the ERs appear to be in interneurons rather than pyramidal or granule cell neurons, (2) ER-ir cells are located in greatest concentration in the hilus of the dentate gyrus and the stratum radiatum of the CA1 region, (3) the density of ER-ir cells exhibits a rostral to caudal gradient in the hilus and the CA1 regions, (4) there are no sex differences in either the number or immunostaining intensity of ER-ir cells in the hippocampus, (5) the ER levels are down-regulated by estrogen in both male and female rats, and (6) the mean intensity of staining for the ER-ir cells in the hippocampus is about 25% of that in the ER-ir cells of the hypothalamus. From this, we can conclude that estrogen can have a direct effect on hippocampal neurons and that any sex differences in estrogen responsiveness is due to something other than sex differences in ER levels or function in the hippocampus.
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