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Human Cortical Organoids with a Novel SCN2A Variant Exhibit Hyperexcitability and Differential Responses to Anti-Seizure Compounds

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Abstract

Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.

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Acknowledgements

We would like to thank Jingyu Liu’s lab for the kind support. We would like to thank the patients and healthy subjects for participating in the study. This work was supported by the National Key R&D Program of China (2022YFC2503802), the National Natural Science Foundation of China (82271499 and 32450530), the Joint Project of the Yangtze River Delta Science and Technology Innovation Community (2024CSJZN00600), and the National Key Research and Development Program of China (2024YFA1108000).

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Authors and Affiliations

  1. Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yuling Yang, Yang Cai, Shuyang Wang, Xiaoling Wu, Xin Wang & Jing Ding

  2. State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China

    Jing Ding

  3. Department of Neurology, Zhongshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China

    Zhicheng Shao

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  1. Yuling Yang
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Yang, Y., Cai, Y., Wang, S. et al. Human Cortical Organoids with a Novel SCN2A Variant Exhibit Hyperexcitability and Differential Responses to Anti-Seizure Compounds. Neurosci. Bull. (2025). https://doi.org/10.1007/s12264-025-01429-w

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