Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice

Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect.