Journal Article

Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia

Zhang, Yang, Mikati, Mohamad A., Cui, Jianmin, Yang, Huanghe, Dong, Ping, Hunanyan, Arsen S.

2022

Overview

A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here, we utilized a knockin mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and dyskinesia. The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits and dyskinesia-like behaviors. The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia. A BK channel blocker, paxilline, potently suppresses BK-D434G–induced hyperexcitability and effectively mitigates absence seizures and locomotor deficits in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and dyskinesia. Our findings also suggest that BK inhibition is a promising therapeutic strategy for mitigating BK GOF-induced neurological disorders.

• Publisher: National Academy of Sciences
• Subject: Animals / Biological Sciences / Cerebellum / Channelopathies / Channelopathy / Convulsions & seizures / Dyskinesia / Dyskinesias - genetics / Epilepsy / Epilepsy, Absence - drug therapy / Epilepsy, Absence - genetics / Humans / Large-Conductance Calcium-Activated Potassium Channels - drug effects / Large-Conductance Calcium-Activated Potassium Channels - physiology / Mice / Movement disorders / Neurological diseases / Neurons / Neuroscience / Pathogenesis / Purkinje cells / Pyramidal cells / Seizures