Microglial NLRP3 inflammasome activates neurotoxic in-like mice

The function and regulation of different heterogeneous reactive states of astrocytes in depression remain unclear. Here, we demonstrate that neurotoxic reactive (A1-like) astrocytes are strongly induced, prior to behavioral impairments and dendritic atrophy, in depression-like mice. More interestingly, global or micro-glia-specific knockout of Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific symbolscript depletion is ineffective. Microglial symbolscript ablation also alleviates the neuronal dysfunction induced by A1-like astrocytes both symbolscript symbolscript and symbolscript symbolscript We further show that in microglia the NF-KB pathway activates the NLRP3 inflammasome which in turn activates caspase-1 to induce the secretion of A1 inductors, leading to the production of A1-like astrocytes. Altogether, this study reveals the function of microglial NLRP3 inflammasome in the induction of neurotoxic astrocytes via activating neu-roinflammatory caspase-1 pathway in response to chronic stress and suggests a potential therapeutic strat-egy for depression.