CB1 agonism prolongs time window for estrogen replacement therapy

OBJECTIVE To detect the underlying mechanism of time window for estrogen(E2)replacement treating cognitive decline.METHODS E2 begun 1 week after the ovariectomy(OVXST)or 3 months after the ovariectomy(OVXLT).Learning and memory ability were examined by trace fear memory test and inhibitory avoidance test.LTP and LTD were detected by MED64.High throughput gene expression sequencing and microRNA(miR NA) sequencing were used to detecte the differently expressed genes between OVXSTand OVXLTafter estrogen treatment.RESULTS Subcutaneous injection of E2 improved fear memory formation in both 1 week after ovariectomy(OVXST) mice or 3 months after ovariectomy(OVXLT) mice.However,for fear memory extinction,facilitated by E2 in OVXSTmice,but impaired by E2 in OVXLTmice.Further researches showed in medial prefrontal cortex(mPFC),estrogen facilitates LTD in OVXSTmice but impairs LTD in OVXLTmice.Results of highthroughput sequencings of mR NA and miRNA in mPFC from sham,OVXSTmice,E2 treated OVXST mice,OVXLTmice,and E2 treated OVXLTmice indicated decreased miR-221-5 p expression in OVXLTmice compared with OVXSTmice.In OVXLT mice,miR-221-5 p could be further reduced by E2 treatment.Additionally,miR-221-5 p targeted neuralized E3 ubiquitin protein ligase 1 a/b(Neurl1 a/b) m RNA.Decreased miR-221-5 p will promotes cannabinoid receptor 1(CB1) ubiquitination through up-regulating Neurl1 a/b protein levels in E2 treated OVXLTmice,which disrupted the retrograde endocanabinoids system.Replenishing miR-221-5 p or treating with CB1 agonist rescued the fear extinction impairment in E2 treated OVXLTmice.CONCLUSION These results uncovered a epigenetic change after long term E2 responsible for failure of E2 improving cognitive performance in OVXLTmice,moreover miR-221-5 p and CB1 agonist as potential targets for prolonging the time window for E2 replacement therapy.