Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Dong, P; Zhang, Y; Hunanyan, AS; Mikati, MA; Cui, J; Yang, H
Published Date
- March 22, 2022
Published In
Volume / Issue
- 119 / 12
Start / End Page
- e2200140119 -
PubMed ID
- 35286197
Pubmed Central ID
- PMC8944272
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.2200140119
Language
- eng
Conference Location
- United States