MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons  

作　　者：Bhupender Sharma Melissa MTorres Sheryl Rodriguez Laxman Gangwani Subodh Kumar 

机构地区：[1]Center of Emphasis in Neuroscience,Department of Molecular and Translational Medicine,Paul L.Foster School of Medicine,Texas Tech University Health Sciences Center,El Paso,TX,USA [2]Bond Life Sciences Center and Department of Veterinary Pathobiology,University of Missouri,Columbia,MO,USA [3]L.Frederick Francis Graduate School of Biomedical Sciences,Texas Tech University Health Sciences Center,El Paso,TX,USA

出　　处：《Neural Regeneration Research》2024年第12期2698-2707,共10页中国神经再生研究（英文版）

基　　金：supported by the National Institute on Aging (NIA);National Institutes of Health (NIH);Nos.K99AG065645,R00AG065645;R00AG065645-04S1 (to SK);NIH research grants,NINDS,No.R01 NS115834;NINDS/NIA,No.R01 NS115834-02S1 (to LG)。

摘　　要：Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic s

关 键 词：Alzheimer's disease GABAergic synapse gamma-aminobutyric acid type A receptor subunitα-1(GABRα1) microRNA-502-3p(miR-502-3p) miRNA in situ hybridization PATCH-CLAMP 

分 类 号：R338[医药卫生—人体生理学]