Serotonergic neurotransmission mediated cognitive dysfunction in two mouse models of sepsis‐associated encephalopathy

Background Patients with sepsis‐associated encephalopathy (SAE) often exhibit cognitive impairments. Despite this, the underlying mechanisms of SAE remain largely unexplored. Here, we explored the role of serotonergic neurotransmission in cognitive dysfunction of two mouse models of SAE. Methods The mouse models of SAE were established by injection of lipopolysaccharide (LPS, 10 mg/kg, intraperitoneal) and cecal ligation puncture (CLP) respectively. Barnes maze, new object recognition test and open field test were used to evaluate the effects of fluoxetine (selective serotonin reuptake inhibitor) and cyproheptadine (nonselective 5‐HT2 receptor antagonist) on cognition and motor activity of mice. Additionally, WAY100635 (5‐HT1A receptor antagonist) was co‐administered with fluoxetine to explore the mechanism underlying effect of fluoxetine on cognitive impairments of SAE. Enzyme‐linked immunosorbent assay (ELISA) was performed to determine 5‐HT levels in hippocampus, brainstem and frontal lobe of experimental groups. Results Both LPS‐induced sepsis and CLP induced sepsis resulted in a notable learning deficit. Fluoxetine ameliorated, while cyproheptadine aggravated, cognitive impairment in two classic mouse models of SAE. The cognition‐enhancing effect of fluoxetine is reversed by WAY100635. Decreased 5‐HT levels in hippocampus, brainstem and frontal lobe were observed in LPS septic model and CLP septic model. Notably, both fluoxetine and cyproheptadine significantly increased 5‐HT levels in those brain regions in LPS septic model. Additionally, fluoxetine significantly increased 5‐HT levels in frontal lobe of CLP septic model. Conclusions Our study demonstrated that serotonergic neurotransmission plays a significant role in mechanisms underlying cognitive impairment in SAE. These findings contribute to identification of novel targets to prevent and arrest cognitive impairment in SAE. Septic mice exhibited cognitive dysfunction and decreased 5‐HT in brain region associated with cognition, and cognitive performance was mediated by SSRI and 5‐HT receptor antagonist. Serotonergic neurotransmission plays a significant role in mechanisms underlying cognitive impairment in SAE.