N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy.
Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explore the influence of NAT10-mediated mRNA acetylation on SAE and the mechanisms underlying cognitive dysfunction in this context. SAE was induced in C57BL/6?J male mice through cecal ligation and puncture (CLP) surgery. In vivo, we observed a significant increase in NAT10 expression in the excitatory neurons of the hippocampal the dentate gyrus (DG) in CLP mice, and this change was accompanied by a trend toward an increase in mRNA acetylation. Specific knockout of Nat10 in neurons led to an improvement in cognitive dysfunction in septic mice. Proteomic analysis and RNA immunoprecipitation and real-time quantitative polymerase chain reaction (RIP-qPCR) revealed GABABR1 as a crucial downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, subsequently weakening inhibitory postsynaptic currents in hippocampal DG neurons. Additionally, RNA sequencing (RNA-seq) revealed an increase in hippocampal inflammation post-CLP, characterized by the excessive activation of microglia and the release of inflammatory mediators. These factors were linked to the increased NAT10 expression in neurons. Treatment with PLX3397, a microglia depleting agent, resulted in a reduction in NAT10 and GABABR1 expression in neurons, which correlated with improvements in cognitive dysfunction induced by SAE. Taken together, our findings revealed that after CLP, NAT10 in neurons of the hippocampal DG region promotes GABABR1 expression by acetylating its mRNA, leading to cognitive dysfunction. These findings provide new insights into the molecular pathogenesis of SAE and suggest potential therapeutic targets for addressing cognitive deficits in septic patients. Overall design: To investigate the changes in the gene expression profile in the mouse hippocampus after CLP modeling, we collected hippocampal tissue for RNA sequencing on the first day following CLP modeling in wild-type mice.