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

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 () and Yi Wang ()
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Junli Zhao: Zhejiang Chinese Medical 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
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
Yi Wang: Zhejiang Chinese Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34662-2

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