Objective
Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in one proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels.
Methods
Here we use a Xenopus laevis oocyte based automated two-electrode voltage-clamp assay. The effects of quinidine (100 and 300 µM) are also tested. Using quantitative RT-PCR, the relative levels of mouse brain mKcnt1 mRNA expression are determined.
Results
We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there was a significant group difference in gain-of-function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain-of-function for all mutations studied.
Interpretation
These results establish direction for a targeted therapy and potentially exemplify a translational paradigm for in vitro studies informing novel therapies in a neuropsychiatric disease.
Cognitive activity resulted in increased flow of blood to the cerebral hemispheres. The increase was greater to the left hemisphere for a verbal task and greater to the right hemisphere for a spatial task. The direction and degree of hemispheric flow asymmetry were influenced by sex and handedness, females having a higher rate of blood flow per unit weight of brain, and females and left-handers having a greater percentage of fast-clearing tissue, presumably gray matter.
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