Low-frequency stimulation in the zona incerta attenuates seizure via driving GABAergic neuronal activity

Mengdi Zhang; Lin Yang; Zhongxia Li; Fan Fei; Yuan Zhou; Dongxiao Jiang; Yuyi Zheng; Hui Cheng; Yu Wang; Cenglin Xu; Jiajia Fang; Shuang Wang; Zhong Chen; Yi Wang

Neurobiology of Disease (Mar 2024)

Low-frequency stimulation in the zona incerta attenuates seizure via driving GABAergic neuronal activity

Mengdi Zhang,
Lin Yang,
Zhongxia Li,
Fan Fei,
Yuan Zhou,
Dongxiao Jiang,
Yuyi Zheng,
Hui Cheng,
Yu Wang,
Cenglin Xu,
Jiajia Fang,
Shuang Wang,
Zhong Chen,
Yi Wang

Affiliations

Mengdi Zhang: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Rehabilitation Medical Center, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
Lin Yang: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China; First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
Zhongxia Li: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Fan Fei: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Yuan Zhou: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Dongxiao Jiang: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Yuyi Zheng: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Hui Cheng: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Yu Wang: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Cenglin Xu: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
Jiajia Fang: Epilepsy Center, Department of Neurology, Second Affiliated Hospital & Forth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
Shuang Wang: Epilepsy Center, Department of Neurology, Second Affiliated Hospital & Forth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
Zhong Chen: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Epilepsy Center, Department of Neurology, Second Affiliated Hospital & Forth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China; Corresponding authors at: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China.
Yi Wang: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Rehabilitation Medical Center, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China; Epilepsy Center, Department of Neurology, Second Affiliated Hospital & Forth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China; Corresponding authors at: Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China.

Journal volume & issue: Vol. 192
p. 106424

Abstract

Read online

Background: Managing refractory epilepsy presents a significant a substantial clinical challenge. Deep brain stimulation (DBS) has emerged as a promising avenue for addressing refractory epilepsy. However, the optimal stimulation targets and effective parameters of DBS to reduce seizures remian unidentified. Objectives: This study endeavors to scrutinize the therapeutic potential of DBS within the zona incerta (ZI) across diverse seizure models and elucidate the associated underlying mechanisms. Methods: We evaluated the therapeutic potential of DBS with different frequencies in the ZI on kainic acid (KA)-induced TLE model or M1-cortical seizures model, pilocarpine-induced M1-cortical seizure models, and KA-induced epilepsy model. Further, employing calcium fiber photometry combined with cell-specific ablation, we sought to clarified the causal role of ZI GABAergic neurons in mediating the therapeutic effects of DBS. Results: Our findings reveal that DBS in the ZI alleviated the severity of seizure activities in the KA-induced TLE model. Meanwhile, DBS attenuated seizure activities in KA- or pilocarpine-induced M1-cortical seizure model. In addition, DBS exerts a mitigating influence on KA induced epilepsy model. DBS in the ZI showed anti-seizure effects at low frequency spectrum, with 5 Hz exhibiting optimal efficacy. The low-frequency DBS significantly increased the calcium activities of ZI GABAergic neurons. Furthermore, selective ablation of ZI GABAergic neurons with taCasp3 blocked the anti-seizure effect of low-frequency DBS, indicating the anti-seizure effect of DBS is mediated by the activation of ZI GABAergic neurons. Conclusion: Our results demonstrate that low-frequency DBS in the ZI attenuates seizure via driving GABAergic neuronal activity. This suggests that the ZI represents a potential DBS target for treating both hippocampal and cortical seizure through the activation of GABAergic neurons, thereby holding therapeutic significance for seizure treatment.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

About the journal

Abstract

Keywords