miR-669g-mediated Tryptophan hydroxylase 2 inhibition induces behavioral abnormalities via modulating the central 5-HT activity in mice

Abstract Tryptophan hydroxylase 2 (TPH2) is a crucial enzyme that plays a rate-limiting role in the biosynthesis of central serotonin (5-HT), and its dysfunction has been associated with various behavioral abnormalities. Investigating miRNAs that target and regulate TPH2 is crucial, as it can provide insights into the molecular mechanisms underlying serotonin synthesis and its potential impact on behavior. In this study, bioinformatics analysis and a dual-luciferase reporter assay identified miR-669g as a regulator of TPH2. Transfection of HT-22 cells with miR-669g resulted in the downregulation of TPH2 expression in vitro. To evaluate the in vivo function of miR-669g, an adeno-associated viral vector-PHP.eB expressing miR-669g was intravenously administered to mice. Subsequent behavioral analyses revealed that the downregulation of TPH2 led to reduced anxiety, impaired memory, and increased aggression, likely through the inhibition of serotonin synthesis. In conclusion, these findings suggest that miR-669g has potential implications for the diagnosis and treatment of behavioral abnormalities.