Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

中文翻译：

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GSDMD/Drp1信号通路介导脓毒症相关脑病小鼠模型海马突触损伤和神经振荡异常

Gasdermin D (GSDMD) 介导的焦亡细胞死亡与脓毒症相关脑病 (SAE) 认知缺陷的发病机制有关，但其潜在机制仍不清楚。动力相关蛋白 1 (Drp1) 促进线粒体裂变并确保质量控制，以维持感染期间的细胞稳态。本研究旨在探讨 GSDMD/Drp1 信号通路在 SAE 小鼠模型认知障碍中的潜在作用。采用C57BL/6雄性小鼠进行盲肠结扎穿刺(CLP)建立SAE动物模型。在介入研究中，小鼠接受了 GSDMD 抑制剂 necrosulfonamide (NSA) 或 Drp1 抑制剂线粒体分裂抑制剂-1 (Mdivi-1) 治疗。对存活的小鼠进行行为学测试，并在相应时间点采集海马组织进行组织学分析和生化检测。苏木精-伊红染色和TUNEL测定用于评估神经元损伤。高尔基染色用于检测突触树突棘密度。此外，还进行了透射电子显微镜来评估海马体中的线粒体和突触形态。进行局部场电位记录以检测海马体中的网络振荡。 CLP 诱导 GSDMD 激活，Drp1 上调，导致相关线粒体损伤、神经炎症以及神经元和突触损伤。因此，这些效应导致海马体神经振荡减少，并导致小鼠显着的学习和记忆缺陷。值得注意的是，用 NSA 或 Mdivi-1 治疗可有效预防这些 GSDMD 介导的异常。我们的数据表明 GSDMD/Drp1 信号通路与 SAE 小鼠模型的认知缺陷有关。抑制 GSDMD 或 Drp1 成为一种潜在的治疗策略，可减轻 SAE 小鼠海马中观察到的突触损伤和网络振荡异常。