Deep brain stimulation (DBS) of the cingulated gyrus 25 is currently evaluated as a new therapy inpatients with treatment-resistant major depressive disorder. The effects of infralimbic prefrontal cortexDBS on several pre-clinical markers of the antidepressant-like response were assessed in rats toinvestigate the mechanisms underlying DBS action, and particularly, the putative involvement of glialsystem. The present study, using electrophysiological, immunohistochemical and behavioralapproaches, shows that acute DBS (130 Hz, 150 μA) induced an antidepressant-like behavior(evaluated in the forced-swim test) that was associated with an increase of dorsal raphe 5-HTneuronal activity and of dentate gyrus neurogenesis. Moreover, acute DBS was able to reverse theeffects of stress on hippocampal synaptic metaplasticity. Besides, DBS at lower intensity (20 μA, 130Hz) induced pro-cognitive effects, i.e. facilitated the hippocampal synaptic metaplasticity and improvedlearning performance in the novel object recognition task. Importantly, these neurobiological effects ofDBS were prevented by local pharmacological glial lesions with the L-alpha-aminoadipic acid gliotoxin.Taken together, our in and ex vivo findings highlights for the first time the crucial role of glial cells inthe mechanism of action of DBS. The present study, therefore, proposes that an unaltered glial systemwithin stimulation areas may constitute a major prerequisite to optimize DBS efficacy
