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We examined the effects of electroconvulsive seizures (ECS) on chronic neuroinflammation and microglial neurotoxicity. Electric brain stimulation inducing full tonic-clonic seizures during chronic relapsing\u2013progressive experimental autoimmune encephalomyelitis (EAE) reduced spinal immune cell infiltration, reduced myelin and axonal loss, and prevented clinical deterioration. Using the transfer EAE model, we examined the effect of ECS on systemic immune response in donor mice versus ECS effect on CNS innate immune activity in recipient mice. ECS did not affect encephalitogenicity of systemic T cells, but it targeted the CNS directly to inhibit T cell\u2013induced neuroinflammation. In vivo and ex vivo assays indicated that ECS suppressed microglial neurotoxicity by reducing inducible NOS expression, nitric oxide, and reactive oxygen species (ROS) production, and by reducing CNS oxidative stress. Microglia from ECS-treated EAE mice expressed less T cell stimulatory and chemoattractant factors. Our findings indicate that electroconvulsive therapy targets the CNS innate immune system to reduce neuroinflammation by attenuating microglial neurotoxicity. 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