Rapid neural Fos responses to oestradiol in oestrogen receptor alphabeta double knockout mice

The standard mode of action for oestradiol is via activation of nuclear oestrogen receptors (ERs), which initiate DNA transcription leading to protein formation. In the present study, we examined the rapid and potentially ER-independent action of oestradiol using Fos as a marker of neural activity. We assessed Fos immunoreactivity (ir) in brains of mice with functional versus nonfunctional ERs. Fos-ir was compared in brains of control mice that did and did not receive oestradiol treatment prior to sacrifice, and cell numbers in the preoptic area (POA), ventromedial nucleus of the hypothalamus (VMH), area 2 of cingulate cortex (CG2), granular layer of accessory olfactory bulb (Gr-AOB), olivary pretectal nucleus (OPT) and pyramidal layer of field CA3 of hippocampus (Py-CA3) were increased 90 min after oestradiol treatment. By contrast, in brains of double oestrogen receptor alphabeta knockout (ERalphabetaKO) female mice, no change in Fos-ir was noted after oestradiol treatment in the POA, VMH, Gr-AOB or Py-CA3, suggesting that these responses to oestradiol depend on ERalpha and/or ERbeta. However, Fos-ir was induced by oestradiol in the OPT and CG2 in ERalphabetaKO mice. These regions do not contain ERalpha-ir in control brains. In ERalphabetaKO brains as well, ERalpha-ir was absent, suggesting that the mutant ERalpha (E1) present in ERalphaKO brain is also absent in these regions. We speculate that oestradiol has rapid effects in the OPT and CG2 via a novel mechanism that does not require either classic oestrogen receptor.