Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase PMID: 36414629

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2022 Nov 21;13(1):7136. doi: 10.1038/s41467-022-34662-2.

Junli Zhao ^# ¹ ² , Jinyi Sun ^# ² , Yang Zheng ¹ , Yanrong Zheng ¹ , Yuying Shao ² , Yulan Li ¹ , Fan Fei ¹ ² , Cenglin Xu ¹ , Xiuxiu Liu ² , Shuang Wang ³ , Yeping Ruan ¹ , Jinggen Liu ¹ , Shumin Duan ⁴ , Zhong Chen ⁵ ⁶ ⁷ , Yi Wang ⁸ ⁹ ¹⁰

Affiliations

1. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
2. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
3. Epilepsy Center, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
4. Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
5. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China. [email protected].
6. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
7. Epilepsy Center, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
8. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China. [email protected].
9. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
10. Epilepsy Center, Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
# Contributed equally.

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.