Medicine (Austin & Northern Health) - Research Publications

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Author: Berkovic, Samuel × Author: Petrou, Steven × Author: Reid, Christopher × Author: Scheffer, Ingrid × End date: 2014 × Start date: 2014 ×

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    KCNT1 Gain of Function in 2 Epilepsy Phenotypes is Reversed by Quinidine
    Milligan, CJ ; Li, M ; Gazina, EV ; Heron, SE ; Nair, U ; Trager, C ; Reid, CA ; Venkat, A ; Younkin, DP ; Dlugos, DJ ; Petrovski, S ; Goldstein, DB ; Dibbens, LM ; Scheffer, IE ; Berkovic, SF ; Petrou, S (WILEY, 2014-04)
    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 1 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 2-electrode voltage clamp assay. The effects of quinidine (100 and 300 μM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, 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 is 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.
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    Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome
    Reid, CA ; Leaw, B ; Richards, KL ; Richardson, R ; Wimmer, V ; Yu, C ; Hill-Yardin, EL ; Lerche, H ; Scheffer, IE ; Berkovic, SF ; Petrou, S (OXFORD UNIV PRESS, 2014-06)
    Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.