2. Academic Validation
  3. Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase

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

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.
PMID: 36414629 DOI: 10.1038/s41467-022-34662-2
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.

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