CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice

Hormone therapy (HT) has proven to be deficient in improving learning and memory in long term menopause according to recent clinical studies; however, the reason for failure of HT improving cognitive performance is unknown. A "window of opportunity" for estrogen treatment is proposed to explain this deficiency of HT. Facilitation of memory extinction and long-term depression by 17β-Estradiol (E2) was normal in mice 1 week after ovariectomy (OVXST), but it was impaired in mice 3 months after ovariectomy (OVXLT). High-throughput sequencing revealed a decrement in miR-221-5p that promoted cannabinoid receptor 1 (CB1) ubiquitination by Neurl1a/b in E2-treated OVXLT mice. Blood samples from menopausal women aged 55–65 indicated decreases in miR-221-5p and 2-AG compared to perimenopausal women aged 46-55 (24.6%±6.8% and 78.8%±7.0%, respectively) Replenishing miR-221-5p or co-treatment with a CB1 agonist and E2 rescued the impairment of fear extinction in OVXLT mice. Present study is the first demonstration that an HT time window in mice can be prolonged by co-treatment with a CB1 agonist.