Abstract
Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. However, both the aetiology of MDD and the mechanisms of action of antidepressants are not completely understood. Many indications suggest the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode for two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is inversely correlated to the cortical density of PV-neurons and to anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1 which, in humans, has been identified as the most central hub gene in the interneuron module downregulated in schizophrenia and ASD. PV-neurons are complex inhibitory interneurons affected in many neuro-psychiatric conditions including MDD and schizophrenia. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are inversely correlated with immobility time in the forced swimming test, an assay used to study of depressive-like behaviours and the efficacy of anti-depressive drugs in rodents. We show that the administration of the antidepressant Fluoxetine (Flx) to normal mice induces, within 24h, a rapid and stable reduction of Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB cascade and can counteract the behavioural and cellular alterations induced by experimental Dlx5 overexpression. Our findings show that one of the short-term effects of Flx treatment is the reduction of Dlx5/6 expression in GABAergic neurons, which, in turn has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients’ response to treatment and can constitute a target for further understanding the mechanism of action of antidepressants.