MicroRNA-669g impairs serotonin balance through TPH2 downregulation and induces behavioral deficits

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.