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

Molecular Therapy: Nucleic Acids

Shuai Zhang¹  Dan Su¹  Lu Zeng¹  Junkai Yang¹  Jing Ai¹  Yi Xu¹  Yang Qu¹  Jing Ma¹  Xin Tang¹  Siyu Huang¹  Xiaobin An¹ 

[1] Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China;

关键词: miR-23a-3p;    PKCα;    aryl hydrocarbon receptor;    memory;    OVX;    aging;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 22-month-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 α (PKCα) protein. Quantitative real-time PCR analysis showed upregulated miRNA-23a-3p (miR-23a-3p) in the hippocampus of 5-month OVX and 22-month-old female mice. In vitro, overexpression of miR-23a-3p downregulated PKCα 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 PKCα 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 PKCα 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/PKCα axis. The knockdown of miR-23a-3p may be a potentially valuable therapeutic strategy for estrogen deficiency-induced memory deficits.

【 授权许可】

Unknown