Down-regulation of RIPK3 prevents depression-like behaviors by restoring the synaptic plasticity and suppressing neuronal loss

Abstract

BackgroundThe excessive secretion of glucocorticoids resulting from the overactivation of the hypothalamic-pituitary-adrenal axis is a crucial factor in the pathogenesis of depression. RIPK3 plays a significant role in apoptosis and necroptosis. Glucocorticoids have been implicated in directly regulating the expression of RIPK3, leading to apoptosis and necroptosis of osteoblasts. This suggests that RIPK3 may contribute to cell death induced by glucocorticoids. However, the precise involvement of RIPK3 in glucocorticoid-induced depression remains poorly understood. MethodsIn this study, a mouse model of depression was established by repeated corticosterone injections to examine the impact of RIPK3 knockdown on depression-like behavior. Additionally, a corticosterone-induced HT22 injury model was also established to investigate the role of RIPK3 in corticosterone-induced neuronal cell death and underlying mechanisms. ResultsOur findings demonstrate that hippocampal RIPK3 knockdown effectively ameliorated depression-related symptoms and restored synaptic plasticity impairment caused by corticosterone. Furthermore, treatment with the RIPK3 inhibitor GSK872 in vitro successfully mitigated corticosterone-induced HT22 cell death. Additionally, the administration of a free radical scavenger alleviated neuronal death and effectively suppressed the expression of corticosterone-induced RIPK3. LimitationsThe limitation of this study is that only the changes of RIPK3 in the hippocampus of depressed male animals were studied. ConclusionsThese results suggest that corticosterone may induce RIPK3-dependent neuronal cell death and impair synaptic plasticity through the generation of high levels of oxidative stress, ultimately leading to depression-like behavior.