Selective estrogen receptor modulators regulate phasic activation of hippocampal CA1 pyramidal cells by estrogen.

Previous studies demonstrated that estrogen induces two sequential waves of CA1 pyramidal cell activation, evidenced by induction of c-Fos at 2 and 24 h after a single estrogen treatment. The second wave of activation is paralleled by suppression of immunoreactivity for glutamic acid decarboxylase-65kD (GAD65) in CA1 and decreased synaptic inhibition of CA1 pyramidal cells. Here, we report that pretreatment with either of the selective estrogen receptor (ER) modulators, tamoxifen (T) or CI628, has no effect on the first wave of c-Fos expression at 2 h but completely blocks the second wave of c-Fos and the suppression of GAD65 at 24 h. Interestingly, T, given 4 h after estrogen, failed to block c-Fos expression or suppression of GAD65 at 24 h. Electrophysiological experiments showed that the T metabolite, 4OH-T, or CI628 can inhibit the so-called rapid estrogen effect, to potentiate excitatory postsynaptic currents (EPSCs) in CA1 pyramidal cells. Thus, estrogen seems to act within 4 h via classical ERs and/or a rapid estrogen effect, such as EPSC potentiation, to produce activation/disinhibition of pyramidal cells 24 h later. In contrast, the initial activation of pyramidal cells, at 2 h after estrogen, seems to involve neither classical ERs nor rapid potentiation of EPSCs.