The Midline Thalamus: The New Kid in Town for Absence Seizure Therapy

Attenuating Midline Thalamus Bursting to Mitigate Absence Epilepsy Dong P, Bakhurin K, Li Y, Mikati MA, Cui J, Grill WM, Yin HH, Yang H. Attenuating midline thalamus bursting to mitigate absence epilepsy. Proc Natl Acad Sci USA. 2024 Jul 9;121(28):e2403763121. doi: 10.1073/pnas.2403763121 . Epub 2024 Jul 5. PMID: 38968111; PMCID: PMC11252967. 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.