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Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase

Author

Listed:
  • Junli Zhao

    (Zhejiang Chinese Medical University
    Zhejiang University)

  • Jinyi Sun

    (Zhejiang University)

  • Yang Zheng

    (Zhejiang Chinese Medical University)

  • Yanrong Zheng

    (Zhejiang Chinese Medical University)

  • Yuying Shao

    (Zhejiang University)

  • Yulan Li

    (Zhejiang Chinese Medical University)

  • Fan Fei

    (Zhejiang Chinese Medical University
    Zhejiang University)

  • Cenglin Xu

    (Zhejiang Chinese Medical University)

  • Xiuxiu Liu

    (Zhejiang University)

  • Shuang Wang

    (Zhejiang University)

  • Yeping Ruan

    (Zhejiang Chinese Medical University)

  • Jinggen Liu

    (Zhejiang Chinese Medical University)

  • Shumin Duan

    (Zhejiang University)

  • Zhong Chen

    (Zhejiang Chinese Medical University
    Zhejiang University
    Zhejiang University)

  • Yi Wang

    (Zhejiang Chinese Medical University
    Zhejiang University
    Zhejiang University)

Abstract

Epileptic seizures are widely regarded to occur as a result of the excitation-inhibition imbalance from a neuro-centric view. Although astrocyte-neuron interactions are increasingly recognized in seizure, elementary questions about the causal role of astrocytes in seizure remain unanswered. Here we show that optogenetic activation of channelrhodopsin-2-expressing astrocytes effectively attenuates neocortical seizures in rodent models. This anti-seizure effect is independent from classical calcium signaling, and instead related to astrocytic Na+-K+-ATPase-mediated buffering K+, which activity-dependently inhibits firing in highly active pyramidal neurons during seizure. Compared with inhibition of pyramidal neurons, astrocyte stimulation exhibits anti-seizure effects with several advantages, including a wider therapeutic window, large-space efficacy, and minimal side effects. Finally, optogenetic-driven astrocytic Na+-K+-ATPase shows promising therapeutic effects in a chronic focal cortical dysplasia epilepsy model. Together, we uncover a promising anti-seizure strategy with optogenetic control of astrocytic Na+-K+-ATPase activity, providing alternative ideas and a potential target for the treatment of intractable epilepsy.

Suggested Citation

  • Junli Zhao & Jinyi Sun & Yang Zheng & Yanrong Zheng & Yuying Shao & Yulan Li & Fan Fei & Cenglin Xu & Xiuxiu Liu & Shuang Wang & Yeping Ruan & Jinggen Liu & Shumin Duan & Zhong Chen & Yi Wang, 2022. "Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34662-2
    DOI: 10.1038/s41467-022-34662-2
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    References listed on IDEAS

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    1. Marta Gómez-Gonzalo & Gabriele Losi & Angela Chiavegato & Micaela Zonta & Mario Cammarota & Marco Brondi & Francesco Vetri & Laura Uva & Tullio Pozzan & Marco de Curtis & Gian Michele Ratto & Giorgio , 2010. "An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold," PLOS Biology, Public Library of Science, vol. 8(4), pages 1-19, April.
    2. Gertrudis Perea & Aimei Yang & Edward S. Boyden & Mriganka Sur, 2014. "Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    3. Mengmeng Du & Jiajia Li & Liang Chen & Yuguo Yu & Ying Wu, 2018. "Astrocytic Kir4.1 channels and gap junctions account for spontaneous epileptic seizure," PLOS Computational Biology, Public Library of Science, vol. 14(3), pages 1-19, March.
    4. Zhibing Tan & Yu Liu & Wang Xi & Hui-fang Lou & Liya Zhu & Zhifei Guo & Lin Mei & Shumin Duan, 2017. "Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
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