Attenuating midline thalamus bursting to mitigate absence epilepsy

Proc Natl Acad Sci U S A. 2024 Jul 9;121(28):e2403763121. doi: 10.1073/pnas.2403763121. Epub 2024 Jul 5.

Abstract

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.

Keywords: BK channelopathy; absence seizure; epilepsy; midline thalamus; thalamus.

MeSH terms

  • Animals
  • Deep Brain Stimulation / methods
  • Disease Models, Animal*
  • Epilepsy, Absence* / physiopathology
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism
  • Male
  • Mice
  • Midline Thalamic Nuclei / physiology
  • Neurons / metabolism
  • Neurons / physiology
  • Optogenetics
  • Thalamus / physiopathology

Substances

  • Large-Conductance Calcium-Activated Potassium Channels