Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation

• The antidepressant effect of prefrontal cortex DBS was prevented by neuronal lesion and adenosine A1 receptor antagonists.
• DBS rapidly increased hippocampal mitosis, cortical oscillations, raphe 5-HT firing activity and synaptogenesis.
• Local glial lesions prevented the neurobiological effects of DBS in a frequency-dependent manner.
• Although deep brain stimulation (DBS) is a promising therapy for patients with treatment-resistant depression, the neurobiological bases underlying its therapeutic action remain largely unknown. Here, we demonstrated that DBS produced a robust antidepressant-like effect that was associated with a fast induction of markers of the antidepressant-like response. Unambiguously, the effects of high-frequency, but not low-frequency, DBS were counteracted by a glial lesion within the site of stimulation. Thus, it is proposed that an unaltered neuronal–glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency of DBS could heighten antidepressant response of partial responders.

Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K+ buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal–glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.