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.
Highlights
THE MAJORITY OF MUTATIONS causing epilepsy occur in ion channel or neurotransmitter receptor genes (Noebels 2003)
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 (GEFSϩ) exhibit a heatinduced 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)
Summary
THE MAJORITY OF MUTATIONS causing epilepsy occur in ion channel or neurotransmitter receptor genes (Noebels 2003). The observation that channel properties varied with expression system limited the conclusions drawn from these studies (George 2005; Lossin et al 2003; Mantegazza et al 2010; Spampanato et al 2003) To circumvent these problems, recent studies have made use of two mouse knock-in models of SCN1A epilepsy: R1407X DS and R1648H GEFSϩ (Martin et al 2010; Ogiwara et al 2007). Located in different regions of the channel, both mutations result in constitutively reduced sodium currents, suggesting loss-of-function mutations that inhibit repetitive firing in GABAergic neurons may be a common mechanism underlying seizures caused by SCN1A mutations. In GABAergic interneurons, this leads to prolonged depolarization that results in reduced repetitive firing (Sun et al 2012) These data suggest that both gain- and loss-of-function SCN1A mutations can result in epileptic activity, and understanding the cellular mechanism of distinct mutations will be important for treating these disorders. We present evidence implicating the serotonin pathway as a novel therapeutic target for DS
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