title: Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current.
abstract: Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene para results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California; Department of Anatomy and Neurobiology, University of California, Irvine, California;
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Schutte
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California; Department of Anatomy and Neurobiology, University of California, Irvine, California;
authors.forename: Soleil S
authors.initials: SS
authors.lastname: Schutte
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California;
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Algara
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California;
authors.forename: Eden V
authors.initials: EV
authors.lastname: Barragan
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: Jeff
authors.initials: J
authors.lastname: Gilligan
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Staber
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: Yiannis A
authors.initials: YA
authors.lastname: Savva
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, California;
authors.forename: Martin A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: Robert
authors.initials: R
authors.lastname: Reenan
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California; Department of Anatomy and Neurobiology, University of California, Irvine, California; dkodowd@uci.edu.
authors.forename: Diane K
authors.initials: DK
authors.lastname: O'Dowd
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D004330:Drosophila / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000378:metabolism; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012701:Serotonin / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D012701:Serotonin; D012964:Sodium; D006916:5-Hydroxytryptophan
keywords: Dravet syndrome; Drosophila; GEFS+; SCN1A epilepsy; sodium channel