Abstracts

This is a Late Breaking abstract

Rationale: Absence epilepsy, characterized by spike-and-wave discharges (SWDs) with lapses of awareness and behavior, is a common pediatric epilepsy that affects numerous children. Unfortunately, about 30% of absence epilepsy patients are resistant to current anti-absence medicines. It is therefore urgent to identify novel anti-absence targets and further understand the molecular, cellular and circuit mechanisms of absence seizures. Recently, we characterized a humanized absence seizure mouse model carrying a gain-of-function D434G mutation of BK large-conductance potassium channel (Dong et al, PNAS, 2022). The BK-D434G mice fully recapitulate the clinical features of the human patients with frequent absence seizures and concurrent behavioral arrest. Pharmacological inhibition of BK channel effectively alleviates the neuronal hyperactivity and suppresses absence seizures. All these findings suggest that inhibiting BK channel could be a novel anti-absence strategy. Our BK-D434G mice can be used as a highly relevant animal model to further uncover new cellular and circuit mechanisms for absence seizure pathogenesis. The overarching goal of this project is to utilize the BK-D434G mice to identify the key brain regions and circuits that contribute to absence seizure and discover novel therapeutic options.

Methods: The BK-D434G and the low dose PTZ (20 mg/kg, i.p.)-treated mice were used as two different absence seizure mouse models. Multi-unit recording in the MDT was combined with EEG-video recording to monitor neuronal activities of MDT during the onset of the SWD. Whole cell patch clamp recording was performed on brain slices to evaluate the cellular basis of absence seizure genesis. Optogenetic stimulation was applied to the brain regions injected with ChR2 to interfere absence seizures during the onset of SWD. Vigilance enhancement was applied to the mice through administration of stimulant drugs such as D-amphetamine or treadmill-induced constant movement perturbation.

Results: Our in vivo electrophysiological recording showed that the MDT neurons from the BK-D434G mice exhibited synchronized burst firing during the onset of the SWD. Our in vitro whole cell patch clamp recording further demonstrated that the BK-D434G MDT neurons had enhanced burst firing. Optogenetic stimulation of the BK-D434G MDT can immediately suppress absence seizures and promote vigilance by switching the firing mode in the MDT from bursting to tonic firing. We also found that administration of stimulants amphetamine or physical perturbation by treadmill can abolish absence seizures in the mouse models.

Conclusions: We demonstrated that synchronized burst firing of the MDT neurons plays an important role in developing absence seizures in one genetic and one chemical-induced mouse models. Switching the MDT neurons from burst to tonic firing via optogenetics efficiently suppresses absence seizures and increases vigilance. The effectiveness physical perturbation and stimulant administration in suppressing SWDs suggests that vigilance enhancement can be a promising therapeutic strategy to treat absence seizures.

Funding: Duke Institute for Brain Sciences (H.Y.), American Epilepsy Society Post-Doctoral Fellowship (P.D.)