Knockdown of SENP7 attenuates cognitive impairment in offspring mice induced by maternal sevoflurane anesthesia partially through cGAS/STING/IRF3-mediated pyroptosis

Abstract

Exposure to sevoflurane (SEV) during pregnancy is associated with long-term cognitive impairment in offspring; however, the precise mechanisms remain unclear. This study aimed to investigate the role of Sentrin/SUMO-specific peptidase 7 (SENP7) and its downstream pathways in SEV-induced neurotoxicity. Pregnant C57BL/6 mice were exposed to 2.5% SEV for 6 h on gestational day 14. Their offspring received bilateral hippocampal injections of AAV-sh-SENP7 or a control virus on postnatal day 21. Cognitive function was assessed using the Morris water maze and contextual fear conditioning tests. Molecular analyses—including qPCR, Western blot, ELISA, and immunofluorescence—were performed to evaluate SENP7 expression, pyroptosis-related responses associated with Iba1-positive myeloid cells, cGAS/STING/IRF3 pathway activation, and neuronal damage. Maternal SEV exposure significantly impaired spatial learning, memory, and contextual fear memory in offspring, concomitant with increased SENP7 expression and enhanced colocalization of SENP7 with Iba1 in the hippocampus. Knockdown of SENP7 effectively rescued these cognitive deficits. Knockdown of SENP7 attenuated SEV-induced Iba1-associated inflammatory activation and pyroptosis-related changes, as evidenced by reduced expression of pyroptosis-related proteins and decreased numbers of Iba1⁺/cleaved Caspase-1⁺ cells. Furthermore, SENP7 knockdown was associated with reduced activation of the cGAS/STING/IRF3 pathway in the hippocampus, accompanied by reduced Iba1/cGAS colocalization. At the neuronal level, SENP7 knockdown ameliorated apoptosis and restored the expression of synaptic proteins (TH, SYN, PSD95, and GAP-43). This study suggests that SENP7 contributes to maternal SEV-induced cognitive impairment, at least in part, in association with cGAS/STING/IRF3 pathway activation and pyroptosis-related responses in Iba1-positive myeloid cells, highlighting SENP7 as a potential therapeutic target for anesthesia-related neurodevelopmental disorders.