
Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia.
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 knock-in 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.
Duke Scholars
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Related Subject Headings
- Seizures
- Neurons
- Mice
- Large-Conductance Calcium-Activated Potassium Channels
- Humans
- Epilepsy, Absence
- Dyskinesias
- Channelopathies
- Animals
Citation

Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Seizures
- Neurons
- Mice
- Large-Conductance Calcium-Activated Potassium Channels
- Humans
- Epilepsy, Absence
- Dyskinesias
- Channelopathies
- Animals