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Background <p>Neonatal exposure to sevoflurane has been implicated in long-term neurodevelopmental abnormalities, yet the underlying mechanisms remain unresolved. This study sought to determine whether cGAS–STING–mediated microglial activation and aberrant synaptic pruning underlie sevoflurane-induced cognitive deficits and to assess how environmental conditions modulate these processes.</p> Methods <p>Neonatal mice underwent sevoflurane exposure followed by rearing in enriched (EE) or impoverished (IE) environments. Cognitive function, synaptic structure, microglial activity, mitochondrial status, and cGAS–STING signaling were evaluated using behavioral tests, immunostaining, biochemical assays, and pharmacological inhibition.</p> Results <p>Sevoflurane exposure induced cognitive impairment, microglial overactivation, mitochondrial dysfunction, and excessive synaptic pruning resulting from microglial overactivation. EE mitigated these abnormalities by preserving mitochondrial integrity and reducing mtDNA-driven cGAS–STING activation, thereby preventing the microglia-mediated imbalance in synaptic pruning and improving cognitive outcomes. In contrast, IE exacerbated mitochondrial injury, aggravated synaptic loss, and further worsened cognitive impairment.</p> Conclusion <p>Sevoflurane disrupts neurodevelopment through a mitochondria–cGAS–microglia–synapse pathway. Environmental enrichment offers significant neuroprotection, highlighting both cGAS–STING signaling and early-life environmental modulation as promising targets for preventing anesthesia-related neurodevelopmental injury.</p> Graphical abstract <p></p>

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Environmental enrichment mitigates sevoflurane-induced neurodevelopmental injury via cGAS–STING–dependent microglial modulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Feixiang Li,
  • Bingqing Gong,
  • Haiyan Wu,
  • Yongyan Yang,
  • Ying Luo,
  • Yonghao Yu,
  • Ding Li

摘要

Background

Neonatal exposure to sevoflurane has been implicated in long-term neurodevelopmental abnormalities, yet the underlying mechanisms remain unresolved. This study sought to determine whether cGAS–STING–mediated microglial activation and aberrant synaptic pruning underlie sevoflurane-induced cognitive deficits and to assess how environmental conditions modulate these processes.

Methods

Neonatal mice underwent sevoflurane exposure followed by rearing in enriched (EE) or impoverished (IE) environments. Cognitive function, synaptic structure, microglial activity, mitochondrial status, and cGAS–STING signaling were evaluated using behavioral tests, immunostaining, biochemical assays, and pharmacological inhibition.

Results

Sevoflurane exposure induced cognitive impairment, microglial overactivation, mitochondrial dysfunction, and excessive synaptic pruning resulting from microglial overactivation. EE mitigated these abnormalities by preserving mitochondrial integrity and reducing mtDNA-driven cGAS–STING activation, thereby preventing the microglia-mediated imbalance in synaptic pruning and improving cognitive outcomes. In contrast, IE exacerbated mitochondrial injury, aggravated synaptic loss, and further worsened cognitive impairment.

Conclusion

Sevoflurane disrupts neurodevelopment through a mitochondria–cGAS–microglia–synapse pathway. Environmental enrichment offers significant neuroprotection, highlighting both cGAS–STING signaling and early-life environmental modulation as promising targets for preventing anesthesia-related neurodevelopmental injury.

Graphical abstract