Zona incerta somatostatin+ neurons modulate seizure progression through hypothalamic circuits

GABAergic neurons critically regulate epileptic seizures, yet circuit mechanisms mediated by subtype-specific GABAergic neurons in the zona incerta (ZI) remain unclear. Here we reveal the essential role of ZI somatostatin+ GABAergic neurons in seizure modulation in the mouse hippocampal kindling model. In vivo Ca2+ fiber photometry and optogenetics show that ZI GABAergic neurons are gradually activated during seizure progression.

Opto-activation inhibits seizure progression, especially the spread of generalized seizures at the later phase, whereas opto-inhibition accelerates it. Although both somatostatin+ and parvalbumin+ neurons are dynamically recruited during seizure progression, only somatostatin+ neurons exert bidirectional seizure modulation. Circuitry mapping and functional modulation demonstrate that ZI somatostatin+ neurons projecting to the ventromedial hypothalamus (VMH) glutamatergic neurons suppress the spread of generalized seizures by inhibiting the excitability of VMH-related downstream seizure-spread regions.

These findings uncover a cell-type-specific circuit mechanism for seizure regulation by ZI somatostatin+ neurons, highlighting these neurons as a potential therapeutic target for epilepsy. We thank members of Chen lab for helpful discussions. Z.C. discloses support for the research of this work from the National Natural Science Foundation of China (82330116).

Y.W. discloses support for the research of this work from National Natural Science Foundation of China (U23A20533), Natural Science Foundation of Zhejiang Province (LD24H310001). M.D.Z. discloses support for the research of this work from National Natural Science Foundation of China (82504775), Natural Science Foundation of Shandong Province (ZR2025QC821). L.Y. discloses support for the research of this work from Natural Science Foundation of Zhejiang Province (LMS25H090012).

These authors contributed equally: Mengdi Zhang, Lin Yang, Yuan Zhou. Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China Mengdi Zhang, Lin Yang, Yuan Zhou, Yeping Ruan, Dongxiao Jiang, Lilong Yu, Jiajia Ying, Wenjing Wang, Tianyu Tang, Menghan Li, Zhong Chen, Fan Fei, Cenglin Xu & Yi Wang Medical Research Center, Shandong Medical and Pharmaceutical University Hospital, Binzhou, China College of Pharmaceutical Sciences, Zhejiang Pharmaceutical University, Ningbo, China Correspondence to Fan Fei, Cenglin Xu or Yi Wang. The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.