Mutations in the SCN1A gene encoding Nav1.1 voltage-gated sodium channels result in a variety of human seizure disorders. These include Dravet Syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Both DS and GEFS+ are autosomal dominant disorders but relatively little is known about the cellular mechanisms underlying seizure generation. Here we propose to assess the functional consequences of disease causing mutations on neuronal activity using two complementary, genetic model systems: knock-in Drosophila with SCN1A mutations and iPSC-derived neurons from patients with the same mutations. Our preliminary data demonstrate that knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semi-dominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS+ flies reveal a novel cellular mechanism underlying heat-induced seizure. Consistent with disease symptoms in humans, the seizure phenotype caused by knock-in of a DS mutation (S1231R) is more severe than GEFS+. The congruence of the genotype-to-phenotype map between flies and human in this genetic disease model paves the way for use of knock-in Drosophila to study the mechanisms underlying these complex human genetic disorders. The first two aims are focused on use of Drosophila sodium channel knock-in lines to further explore the underlying cellular mechanisms contributing to heat-induced seizures and as a low cost, high efficiency, platform for discovery of genetic modifiers and drugs that suppress the seizure phenotype.
In specific Aim 3 we will employ our expertise in stem cell biology to conduct parallel studies of neuronal activity in iPSC-derived neurons from patients with the same GEFS+ mutations examined in knock-in flies. Identification of common cellular mechanisms in these two model systems has the potential to identify targets for development of novel therapies to reduce or eliminate seizures in humans with epilepsy.

Public Health Relevance

There are literally hundreds of mutations in the SCN1A sodium channel gene that result in the human epilepsy disorders Dravet Syndrome and GEFS+. In this proposal we will use knock-in Drosophila with SCN1A mutations and iPSC-derived neurons from patients with the same mutations to explore the underlying disease mechanisms. This two-pronged approach provides a novel platform for defining the cellular mechanisms contributing to heritable seizure disorders and developing new therapies for treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-G (91))
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Whittemore, Vicky R
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University of California Irvine
Anatomy/Cell Biology
Schools of Medicine
United States
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Brick, David J; Nethercott, Hubert E; Montesano, Samantha et al. (2014) The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery. Stem Cells Transl Med 3:1275-86