Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current

• Published in: Journal of neurophysiology Vol. 112; no. 4; pp. 903 - 912
• Main Authors: Schutte, Ryan J, Schutte, Soleil S, Algara, Jacqueline, Barragan, Eden V, Gilligan, Jeff, Staber, Cynthia, Savva, Yiannis A, Smith, Martin A, Reenan, Robert, O'Dowd, Diane K
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.08.2014
• Subjects: 5-Hydroxytryptophan - metabolism; Action Potentials; Animals; Brain - cytology; Brain - metabolism; Brain - physiopathology; Drosophila - genetics; Drosophila - metabolism; Drosophila - physiology; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - metabolism; GABAergic Neurons - metabolism; GABAergic Neurons - physiology; Interneurons - metabolism; Interneurons - physiology; Mutation, Missense; NAV1.1 Voltage-Gated Sodium Channel - genetics; NAV1.1 Voltage-Gated Sodium Channel - metabolism; Neural Circuits; Phenotype; Serotonin - metabolism; Sodium - metabolism; GEFS; sodium channel; SCN1A epilepsy; Drosophila; Dravet syndrome
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00135.2014

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.