Dlx5/6genes encode for two homeobox transcription factors expressed in most forebrain GABAergic neurons, and involved in differentiation of Parvalbumin-positive interneurons (PV). PV interneurons are essential for normal brain function andPV expression is a hallmark of neuronal maturation. Their activity and distribution are altered in psychiatric conditions. Epidemiological studies suggest a link of the Dlx5/6locus with psychiatric disorders such as schizophrenia and autism spectrum disorder.Fluoxetine(FLX) is used to treat depression and anxiety disorders. Its administration induces a juvenile-like state by dematurating PV neurons and reducing Parvalbuminexpression, which could participate in the therapeutic effect of the treatment.Using mouse lines of Dlx5/6invalidation or overexpression in GABAergic neurons, we showed that higher Dlx5 expression is associated with increased anxiety, compulsivity and PV neuronal density in the frontal cortex and hippocampus. In contrast, deletion of Dlx5/6results in reduced anxiety and compulsivity with decrease level of PV in the same regions. Dlx5/6expression level was also correlated with depressive-like behaviours. We showed that FLX induces a reduction of Dlx5/6expression in the cerebral cortex, that was able to compensate the phenotypic alterations caused by a genetic Dlx5overexpression. FLX induces a rapid and sustained inhibition of cortical Dlx5expression through a TrkB-CREB signaling pathway.Our findings suggest that Dlx5/6expression is involved in the regulation of adult anxiety and depressive like behaviours linked with PV-neurons density. Reduction of their expression through genetic approaches or FLX treatment induce an anti-depressive like phenotype.