{"title":"MicroRNA-669g impairs serotonin balance through TPH2 downregulation and induces behavioral deficits.","authors":"Shihui Guo, Yingying Dong, Yujia Shu, Xuanfu Wu, Chenxuan Li, Yingdong Ni, Hongsheng Zhang, Wenqiang Ma","doi":"10.1016/j.bbr.2025.115861","DOIUrl":null,"url":null,"abstract":"<p><p>Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in central serotonin (5-HT) biosynthesis, and its dysfunction has been linked to various behavioral abnormalities. Here, we identify microRNA-669g (miR-669g) as a novel regulator of TPH2. Bioinformatic prediction combined with dual-luciferase reporter assays confirmed that miR-669g directly targets TPH2. In HT-22 cells, miR-669g transfection markedly reduced TPH2 expression. To assess its in vivo function, we delivered an AAV-PHP.eB vector encoding miR-669g systemically into mice. Elevated miR-669g expression in the brain suppressed TPH2 expression, reduced cerebral 5-HT levels, and induced behavioral phenotypes, including increased aggression and impaired memory. These findings uncover a previously unrecognized miRNA-enzyme interaction in 5-HT metabolism and suggest that miR-669g may contribute to neuropsychiatric dysfunction through disruption of serotonergic homeostasis.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"115861"},"PeriodicalIF":2.3000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Behavioural Brain Research","FirstCategoryId":"102","ListUrlMain":"https://doi.org/10.1016/j.bbr.2025.115861","RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in central serotonin (5-HT) biosynthesis, and its dysfunction has been linked to various behavioral abnormalities. Here, we identify microRNA-669g (miR-669g) as a novel regulator of TPH2. Bioinformatic prediction combined with dual-luciferase reporter assays confirmed that miR-669g directly targets TPH2. In HT-22 cells, miR-669g transfection markedly reduced TPH2 expression. To assess its in vivo function, we delivered an AAV-PHP.eB vector encoding miR-669g systemically into mice. Elevated miR-669g expression in the brain suppressed TPH2 expression, reduced cerebral 5-HT levels, and induced behavioral phenotypes, including increased aggression and impaired memory. These findings uncover a previously unrecognized miRNA-enzyme interaction in 5-HT metabolism and suggest that miR-669g may contribute to neuropsychiatric dysfunction through disruption of serotonergic homeostasis.
期刊介绍：
Behavioural Brain Research is an international, interdisciplinary journal dedicated to the publication of articles in the field of behavioural neuroscience, broadly defined. Contributions from the entire range of disciplines that comprise the neurosciences, behavioural sciences or cognitive sciences are appropriate, as long as the goal is to delineate the neural mechanisms underlying behaviour. Thus, studies may range from neurophysiological, neuroanatomical, neurochemical or neuropharmacological analysis of brain-behaviour relations, including the use of molecular genetic or behavioural genetic approaches, to studies that involve the use of brain imaging techniques, to neuroethological studies. Reports of original research, of major methodological advances, or of novel conceptual approaches are all encouraged. The journal will also consider critical reviews on selected topics.
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