AhR/miR-23a-3p/PKCa axis contributes to memory deficits in ovariectomized and normal aging female mice

The mechanism of estrogen deficiency-induced cognitive impairment is still not fully elucidated. In this study, we assessed the effect of microRNA (miRNA) on the memory of long-term estrogen-deficient mice after ovariectomy (OVX) and normal aging. We observed that 5-month OVX and 22month-old normal aging female mice showed significantly impaired spatial and object recognition memory, declined hippocampal long-term potentiation (LTP), and decreased hippocampal protein kinase C a (PKCa) protein. Quantitative real-time PCR analysis showed upregulated miRNA-23a-3p (miR-23a-3p) in the hippocampus of 5-month OVX and 22month-old female mice. In vitro, overexpression of miR-23a3p downregulated PKCa by binding the 3 UTRs of Prkca mRNAs, which was prevented by its antisense oligonucleotide AMO-23a. In vivo, adeno-associated virus-mediated overexpression of miR-23a-3p (AAV-pre-miR-23a-3p) suppressed hippocampal PKCa and impaired the memory of mice. Chromatin immunoprecipitation analysis showed that aryl hydrocarbon receptor (AhR) binds the promoter region of miR-23a-3p. The AhR-dependent downregulation of PKCa could be prevented by AMO-23a as well. Furthermore, knockdown of miR-23a-3p using AAV-AMO-23a rescued the cognitive and electrophysiological impairments of OVX and normal aging female mice. We conclude that long-term estrogen deficiency impairs cognition and hippocampal LTP by activating the AhR/miR-23a-3p/PKCa axis. The knockdown of miR23a-3p maybe a potentially valuable therapeutic strategy for estrogen deficiency-induced memory deficits.

Automated summary

Estrogen deficiency induces cognitive impairment, with miR-23a-3p playing a role in hippocampal function through the AhR/miR-23a-3p/PKCa axis.