Previous Midlife Oestradiol Treatment Results in Long-Term Maintenance of Hippocampal Oestrogen Receptor α Levels in Ovariectomised Rats: Mechanisms and Implications for Memory

Ovariectomised rats that have received previous administration of oestradiol in midlife display enhanced cognition and increased hippocampal levels of oestrogen receptor (ER) months after oestradiol treatment ended compared to ovariectomised controls. The present study aimed to investigate the mechanisms by which ER levels are maintained following midlife oestradiol exposure and the role of ER in memory in ageing females in the absence of circulating oestrogens. Unliganded ER has increased interaction with the ubiquitin ligase, C-terminus of Hsc-70 interacting protein (CHIP), leading to increased degradation of the receptor. In our first experiment, we tested the hypothesis that midlife oestradiol exposure in ovariectomised rats results in decreased interaction between CHIP and hippocampal ER, leading to increased levels of ER. Middle-aged rats were ovariectomised and received oestradiol or vehicle implants. After 40days, implants were removed. One month later, rats were killed and hippocampi were processed for whole protein western blotting and co-immunoprecipitation, in which ER was immunoprecipitated from lysate. As expected, ER protein expression was increased in rats previously treated with oestradiol compared to vehicle-treated rats. In rats treated with oestradiol, there was a decrease in CHIP-ER interaction, suggesting that previous oestradiol treatment reduces interaction, slowing the degradation of ER. In a second experiment, we determined the impact on memory of antagonism of ER in the absence of circulating oestrogens. Rats were ovariectomised and implanted with oestradiol capsules. Capsules were removed after 40days. Rats received chronic i.c.v. infusion of ER antagonist, ICI 182780, or artificial cerebrospinal fluid vehicle and were tested on a spatial memory radial-maze task. Rats treated with ICI 182780 had significantly worse performance (more errors). These experiments provide evidence that previous midlife oestradiol treatment maintains hippocampal ER by decreasing its interaction with CHIP and that activation of these receptors provides cognitive benefits in the absence of circulating oestrogens.