Attenuating midline thalamus bursting to mitigate absence epilepsy

• 成果类型: Article
• 署名作者: Dong, Ping; Bakhurin, Konstantin; Li, Yuhui; Mikati, Mohamad A.; Cui, Jianmin; Grill, Warren M.; Yin, Henry H.; Yang, Huanghe
• 署名单位: Duke University; Duke University; Duke University; Duke University; Duke University; Duke University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12096
• DOI: 10.1073/pnas.2403763121
• 发表日期: 2024-07-09
• 关键词: central-nervous-system; bk channel activation; c-fos expression; seizures; consciousness; stimulation; amphetamine; inhibition; synchrony; Mutation

摘要

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain- of- function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK- D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy.