Yuling Yang1 · Yang Cai1 · Shuyang Wang1 · Xiaoling Wu1 · Zhicheng Shao3 · Xin Wang1 · Jing Ding1,2
1 Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2 State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
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
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.
Keywords
Brain organoid; Genetic epilepsy; SCN2A; Anti-seizure medication; Channelopathy
