Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia

Abstract

Significance BK channelopathy has been increasingly implicated in diverse neurological disorders, including epilepsy and movement, cognitive, and neurodevelopmental disorders. However, precision medicine to treat BK channelopathy is lacking. We characterized a mouse model carrying a gain-of-function BK channelopathy D434G from a large family of patients with absence epilepsy and paroxysmal dyskinesia. The BK-D434G mice manifest the clinical features of absence seizures and exhibit severe locomotor defects including involuntary dyskinesia-like behavior. Pharmacological inhibition of BK channels suppresses neuronal hyperactivity and mitigates absence seizure and the locomotor defects. The BK-D434G mice thus serve as a model to understand the pathogenic mechanisms of absence epilepsy and dyskinesia. Our study also suggests that BK inhibition is a promising strategy for treating BK gain-of-function channelopathy.