Tracking the estrogen receptor in neurons: Implications for estrogen-induced synapse formation

Estrogens (E) and progestins regulate synaptogenesis in the CA1 region of t he dorsal hippocampus during the estrous cycle of the female rat, and the f unctional consequences include changes in neurotransmission and memory. Syn apse formation has been demonstrated by using the Golgi technique, dye fill ing of cells, electron microscopy. and radioimmunocytochemistry. N-methyl-D -aspartate (NMDA) receptor activation is required, and inhibitory interneur ons play a pivotal role as they express nuclear estrogen receptor alpha (ER alpha) and show E-induced decreases of GABAergic activity. Although global decreases in inhibitory tone may be important, a more local role for E in CA1 neurons seems likely. The rat hippocampus expresses both ER alpha and E R beta mRNA. At the light microscopic level, autoradiography shows cell nuc lear [H-3]estrogen and [I-125]estrogen uptake according to a distribution t hat primarily reflects the localization of ER alpha -immunoreactive interne urons in the hippocampus. However, recent ultrastructural studies have reve aled extranuclear ERa immunoreactivity (IR) within select dendritic spines on hippocampal principal cells, axon terminals, end glial processes, locali zations that would not be detectable by using standard light microscopic me thods. Based on recent studies showing that both types of ER are expressed in a form that activates second messenger systems, these findings support a testable model in which local, non-genomic regulation by estrogen particip ates along with genomic actions of estrogens in the regulation of synapse f ormation.