Abstract # 1774 Microglia mediate the anti-depressive effects of electroconvulsive shock therapy in mice exposed to chronic unpredictable stress

Abstract

Electroconvulsive therapy (ECT) is one of the most effective treatments for depression. Although it has been used for decades, particularly for treatment of major depression patients with drug resistance, the mechanisms underlying ECT’s action are still elusive. Recent studies in our laboratory demonstrated that decline in the number and activation status of hippocampal microglia underlies the development of depressive-like symptoms in chronic unpredictable stress (CUS)-exposed mice. Here, we investigated whether the therapeutic effects of ECT are mediated via modulation of microglial status. We specifically assessed whether microglial inhibition (by minocycline administration), or depletion (by chronic treatment with the selective CSF1 receptor kinase inhibitor PLX5622), interferes with the therapeutic effects of ECT in CUS-exposed mice. ECT (3 sessions/week for 2.5 weeks) reversed the CUS-induced reductions in sucrose preference (anhedonia) and social exploration. These effects were microglia-dependent, evidenced by blockade of these therapeutic effects by minocycline, or by the mere absence of brain microglia. ECT-induced increases in hippocampal neurogenesis were also reduced by minocycline. Furthermore, ECT reversed the CUS-induced decrease in the total length of hippocampal microglial processes, but not the reduction in microglial number. Consistent with these morphological changes, ECT significantly altered microglia-related gene transcripts including Csfr1, P2y12r, and P2x7. In conclusion, we show that the anti-depressive therapeutic effects of ECT are dependent on the presence and activity level of microglia in the hippocampus.