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<p>Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP–AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS–STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.</p>

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cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Yige Huang,
  • Li Fan,
  • Man Ying Wong,
  • Zhuofan Lei,
  • Balaji Krishnamachary,
  • Daphne Zhu,
  • Mika P. Cadiz,
  • Ravi Kumar Nagiri,
  • Pearly Ye,
  • Kendra Norman,
  • Maitreyee Bhagwat,
  • Young Jae Lee,
  • Hui Li,
  • Jingjie Zhu,
  • Sadaf Amin,
  • Kelli Lauderdale,
  • Hao Chen,
  • Wenjie Luo,
  • Shiaoching Gong,
  • Benjamin L. Liechty,
  • Jorge J. Palop,
  • Subhash C. Sinha,
  • Junfang Wu,
  • Mingrui Zhao,
  • Li Gan

摘要

Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP–AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS–STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.