Previous midlife estradiol treatment results in long-term maintenance of hippocampal ERα levels in ovariectomized rats: Mechanisms and implications for memory

Abstract

Ovariectomized rats that received previous administration of oestradiol in midlife display enhanced cognition and increased hippocampal levels of oestrogen receptor alpha (ERα) months after oestradiol treatment ended as compared to ovariectomized controls. Objectives of the current work were to investigate mechanisms by which ERα levels are maintained following midlife oestradiol exposure and the role of ERα in memory in aging females in the absence of circuiting oestrogens. Unliganded ERα 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 ovariectomized rats results in decreased interaction between CHIP and hippocampal ERα, leading to increased levels of ERα. Middle-aged rats were ovariectomized and received oestradiol or vehicle implants. After 40 days, implants were removed. One month later, rats were killed and hippocampi processed for whole protein western blotting and co-immunoprecipitation, in which ERα was immunoprecipitated from lysate. As expected, ERα 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-ERα interaction, suggesting that previous oestradiol treatment reduces interaction, slowing degradation of ERα. In a second experiment, we determined the impact on memory of antagonism of ER in the absence of circulating oestrogens. Rats were ovariectomized and implanted with oestradiol capsules. Capsules were removed after 40 days. Rats received chronic i.c.v. infusion of ER antagonist, ICI 182,780 or aCSF vehicle and were tested on a spatial memory radial maze task. Rats treated with ICI 182,780 had significantly worse performance (more errors). These experiments provide evidence that previous midlife oestradiol treatment maintains hippocampal ERα by decreasing its interaction with CHIP and that activation of these receptors provides cognitive benefits in the absence of circulating oestrogens.

This article is protected by copyright. All rights reserved.

http://ift.tt/2c57w8I