Circulating Estradiol Regulates Neurosteroid Estradiol Via Actions At Gnrh Receptors To Impact Memory And The Hippocampus
Peripheral estradiol treatment enhances hippocampus-dependent memory and morphology in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on GnRH activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects cognition and the hippocampus through brain-derived estradiol via hippocampal GnRH receptor activity. In Experiment 1, we investigated if peripheral estradiol exerts its effects through regulation of brain-derived estradiol. Intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task and blocked or attenuated estradiol-induced increases in hippocampal synaptic proteins. In Experiment 2, we investigated if peripheral estradiol affects cognition and the hippocampus through hippocampal GnRH receptors. Hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task and blocked estradiol-induced increases in hippocampal synaptic proteins and aromatase, the final enzyme involved in estradiol synthesis. In Experiment 3A, we investigated whether hippocampal GnRH infusion was sufficient to enhance hippocampus-dependent memory and affect the hippocampus in ovariectomized rats and whether this was dependent on neuroestradiol synthesis. Hippocampal infusion of GnRH enhanced hippocampus-dependent memory in a radial maze task, the effects of which were blocked by letrozole infusion. Unexpectedly, GnRH treatment decreased levels or had no effect on a hippocampal postsynaptic proteins or aromatase. Due to the unexpected molecular results of Experiment 3A, Experiment 3B investigated if shorter treatment of GnRH affects hippocampal proteins differently. As opposed to the 10-12 days of GnRH treatment in Experiment 3A, five days of GnRH treatment increased levels of synaptic proteins via neuroestradiol synthesis as coadministration of letrozole blocked these effects. Results indicate that peripheral estradiol-induced enhancement of cognition and hippocampal morphology is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.