Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites

Estrogen may mediate some of its effects on hippocampal function through th e alpha isoform of the estrogen receptor (ER alpha). By light microscopy, E R alpha -immunoreactivity (-I) is found in the nuclei of scattered inhibito ry gamma -aminobutyric acid (GABA)ergic interneurons. However, several line s of evidence indicate that estrogen also may exert some of its effects thr ough rapid nongenomic mechanisms, possibly by binding to plasma membranes. Thus, to determine whether ER alpha is found in extranuclear sites in the h ippocampal formation (HF), four different antibodies to ER alpha were local ized by immunoelectron microscopy in proestrous rats. Ultrastructural analy sis revealed that in addition to interneuronal nuclei, ER alpha -I was affi liated with the cytoplasmic plasmalemma of select interneurons and with end osomes of a subset of principal (pyramidal and granule) cells. Moreover, ER alpha labeling was found in profiles dispersed throughout the HF, but slig htly more numerous in CA1 stratum radiatum. Approximately 50% of the ER alp ha -labeled profiles were unmyelinated axons and axon terminals that contai ned numerous small, synaptic vesicles. ER alpha -labeled terminals formed b oth asymmetric and symmetric synapses on dendritic shafts and spines, sugge sting that ER alphas arise from sources in addition to inhibitory interneur ons. About 25% of the ER alpha -I was found in dendritic spines, many origi nating from principal cells. Within spines, ER alpha -I often was associate d with spine apparati and/or polyribosomes, suggesting that estrogen might act locally through the ER alpha to influence calcium availability, protein translation,:or synaptic growth. The remaining 25% of ER alpha -labeled pr ofiles were astrocytes, often located near the spines of principal cells. C ollectively, these results suggest that ER alpha may serve as both a genomi c and nongenomic transducer of estrogen action in the HF. J. Comp. Neurol. 429: 355-371, 2001. (C) 2001 Wiley-Liss, Inc.