STING Driving Synaptic Phagocytosis of Hippocampal Microglia/Macrophages Contributes to Cognitive Impairment in Sepsis‐Associated Encephalopathy in Mice

ABSTRACT Background Sepsis‐associated encephalopathy (SAE) is a serious neurologic complication in septic patients with poor prognoses. There is increasing evidence that stimulator of interferon genes (STING) plays a crucial role in neuroinflammation and cognitive impairment. However, whether sepsis associated with STING changes contributes to cognitive impairment is unknown. Methods Male adult mice received lipopolysaccharide (LPS) injection (a single dose of 4 mg/kg; i.p. injection) and 30 min later, they were injected with STING inhibitor C‐176 (a single dose of 30 mg/kg, i.p. injection). Behavioral assessments, biochemical measurements, in vivo and ex vivo electrophysiology techniques were conducted to investigate the association between LPS‐induced STING overexpression and cognitive function. Results Cognitive impairment was associated with STING overexpression and activation of microglia/macrophages. Phagocytosis of microglia/macrophages as well as complement C1q release were increased after LPS injection, leading to abnormal pruning synapses, synaptic transmission reduction, long‐term potentiation (LTP) impairment, as well as abnormal theta oscillation in the hippocampus. Notably, STING inhibitor C‐176 significantly reversed these changes. Conclusions Sepsis‐induced STING overexpression in microglia/macrophages may lead to synaptic loss, abnormal theta oscillation and LTP impairment through microglia/macrophages activation and complement C1q modulation, ultimately resulting in cognitive impairment.