作者：ZHANG; Kun; LI; Yan-jiao; YANG; Qi; LI...cannabinoidreceptor1estrogentimewindowmirnaepigenetic
摘要：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 (miRNA) sequencing were used to detecte the differently expressed genes between OVXST and OVXLT after 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 OVXST mice, but impaired by E2 in OVXLT mice. Further researches showed in medial prefrontal cortex (mPFC), estrogen facilitates LTD in OVXST mice but impairs LTD in OVXLT mice. Results of highthroughput sequencings of mRNA and miRNA in mPFC from sham, OVXST mice, E2 treated OVXST mice, OVXLT mice, and E2 treated OVXLT mice indicated decreased miR-221-5p expression in OVXLT mice compared with OVXST mice. In OVXLT mice, miR-221-5p could be further reduced by E2 treatment. Additionally, miR-221-5p targeted neuralized E3 ubiquitin protein ligase 1a/b (Neurl1a / b) mRNA. Decreased miR-221-5p will promotes cannabinoid receptor 1 (CB1) ubiquitination through up-regulating Neurl1a / b protein levels in E2 treated OVXLT mice, which disrupted the retrograde endocanabinoids system. Replenishing miR-221-5p or treating with CB1 agonist rescued the fear extinction impairment in E2 treated OVXLT mice. CONCLUSION These results uncovered a epigenetic change after long term E2 responsible for failure of E2 improving cognitive performance in OVXLT mice, moreover miR-221-5p and CB1 agonist as potential targets for prolonging the time window for E2 replacement therapy.
注：因版权方要求，不能公开全文，如需全文，请咨询杂志社
