Inhibition of NLRP3 inflammasome-mediated neuroinflammation alleviates electroconvulsive shock-induced memory impairment via regulation of hippocampal synaptic plasticity in depressive rats

Abstract

Electroconvulsive shock has been considered one of the most effective treatment modalities for major depressive disorder. The association of acute transitory neuroinflammation in the hippocampus following electroconvulsive therapy with transient learning and memory impairment limits its clinical application. Whereas the NLRP3 inflammatory pathway is deemed to serve a key role in neuroinflammatory regulation, we aimed to examine if NLRP3 inflammasome activation was linked to electroconvulsive shock (ECS)-induced neuroinflammation and cognitive deficits. The depressed rats were modeled with chronic unpredictable mild stress. Their depression-like behaviors and cognitive performance were evaluated via sucrose preference test, forced swim test, open field test, and Morris water maze test. The NLRP3 expression was determined by western blot. The hippocampal CA1 region was immunohistochemically and electron-microscopically examined, respectively, for the activation of Iba-1 positive microglia and the ultrastructure of synapses. In this work, we found that ECS induced microglial activation in the rat hippocampal CA1 region. Pharmacological inhibition of NLRP3 inflammasome with MCC950 (NLRP3 inhibitor) in vivo significantly alleviated ECS-induced spatial learning and memory impairment, partially reversed neuroinflammation, and synaptic structural plasticity in the damaged hippocampal CA1 region, and reduced synapse associated protein expression and microglial activation. It offers a potential new approach for the prevention and treatment of cognitive decline following electroconvulsive therapy.