Neuronal mechanism of a BK channelopathy in absence epilepsy and movement disorders

Abstract

A growing number of gain-of-function (GOF) BK channelopathy have been identified in patients with epilepsy and paroxysmal movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here we utilized a knock-in mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and movement disorders. We found that the BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits. BK-D434G mutation causes hyperexcitability of cortical pyramidal neurons and cerebellar Purkinje cells, which contributes to the pathogenesis of absence seizures and the motor defects, respectively. A BK channel blocker paxilline potently suppresses BK-D434G-induced hyperexcitability and effectively mitigates absence seizures in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and provided the evidence that BK inhibition is a promising therapeutic strategy to mitigate BK GOF-induced neurological disorders. SignificanceDysfunction of BK channels or BK channelopathy has been increasingly implicated in diverse neurological disorders including epilepsy, movement, cognitive and neurodevelopmental disorders. However, precision medicine to treat BK channelopathy is lacking. Here we characterized a mouse model carrying a gain-of-function BK channelopathy D434G from a large family of patients with absence epilepsy and involuntary movement disorders. The BK-D434G mice resemble the clinical manifestations of absence seizures and exhibit severe motor defects. The hyperexcitability in BK-D434G cortical neurons and cerebellar Purkinje cells underscores the neuronal mechanism of BK gain-of-function induced absence epilepsy and movement disorders. The effectiveness of a BK channel blocker on preventing absence seizures suggests that BK inhibition is a promising strategy to treat gain-of-function BK channelopathy.