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The released neuronal mtDNA induced a robust microglial activation mediated by binding to the cytoplasmic DNA\/RNA sensor Z-DNA\u2013binding protein 1 (ZBP1), triggering activation of the ZBP1\u2013TBK1\u2013IRF3 pathway resulted IL-6 and TNF\u03b1 expression. An early, enhanced amounts of mtDNA, neuronal and exosomal markers were measured in EVs circulating in the blood of mice subjected to mTBI. ZBP1 knockout (KO) mice displayed suppressed microglial\u2014but not astrocytic\u2014activation in the cortex during the acute mTBI phase. We also measured accumulation of mtDNA-specific damage in the hippocampus during the postacute mTBI phase. The absence of microglial activation in ZBP1 KO mice exacerbated hippocampal-related memory deficits in the postacute mTBI phase. 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