title: Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in theDrosophilaVoltage-Gated Sodium Channel Geneparalytic.
abstract: Shudderer(Shu) is an X-linked dominant mutation inDrosophila melanogasteridentified more than 40 years ago. A previous study showed thatShucaused spontaneous tremors and defects in reactive climbing behavior, and that these phenotypes were significantly suppressed when mutants were fed food containing lithium, a mood stabilizer used in the treatment of bipolar disorder (Williamson, 1982). This unique observation suggested that theShumutation affects genes involved in lithium-responsive neurobiological processes. In the present study, we identifiedShuas a novel mutant allele of the voltage-gated sodium (Nav) channel geneparalytic(para). Given that hypomorphicparaalleles and RNA interference-mediatedparaknockdown reduced the severity ofShuphenotypes,Shuwas classified as aparahypermorphic allele. We also demonstrated that lithium could improve the behavioral abnormalities displayed by other Navmutants, including a fly model of the human generalized epilepsy with febrile seizures plus. Our electrophysiological analysis ofShushowed that lithium treatment did not acutely suppress Navchannel activity, indicating that the rescue effect of lithium resulted from chronic physiological adjustments to this drug. Microarray analysis revealed that lithium significantly alters the expression of various genes inShu, including those involved in innate immune responses, amino acid metabolism, and oxidation-reduction processes, raising the interesting possibility that lithium-induced modulation of these biological pathways may contribute to such adjustments. Overall, our findings demonstrate that Navchannel mutants inDrosophilaare valuable genetic tools for elucidating the effects of lithium on the nervous system in the context of neurophysiology and behavior.
authors.affiliation: Interdisciplinary Graduate Program in Genetics, University of Iowa , IA 52242, USA.
authors.forename: Garrett A
authors.identifier: 0000-0002-1916-975X
authors.initials: GA
authors.lastname: Kaas
authors.affiliation: Department of Anesthesia, Carver College of Medicine, University of Iowa , IA 52242.
authors.forename: Junko
authors.initials: J
authors.lastname: Kasuya
authors.affiliation: Interdisciplinary Graduate Program in Genetics, University of Iowa , IA 52242, USA.
authors.forename: Patrick
authors.identifier: 0000-0002-9004-6138
authors.initials: P
authors.lastname: Lansdon
authors.affiliation: Department of Biology, College of Liberal Arts and Sciences, University of Iowa , IA 52242.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ueda
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, University of Iowa , IA 52242.
authors.forename: Atulya
authors.initials: A
authors.lastname: Iyengar
authors.affiliation: Interdisciplinary Graduate Program in Genetics, University of Iowa, IA 52242, USA; Department of Biology, College of Liberal Arts and Sciences, University of Iowa, IA 52242; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, IA 52242.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Wu
authors.affiliation: Interdisciplinary Graduate Program in Genetics, University of Iowa, IA 52242, USA; Department of Anesthesia, Carver College of Medicine, University of Iowa, IA 52242; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, IA 52242.
authors.forename: Toshihiro
authors.identifier: 0000-0003-0863-8466
authors.initials: T
authors.lastname: Kitamoto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018020:Lithium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D049990:Membrane Transport Modulators / Q000493:pharmacokinetics / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D029721:Drosophila Proteins; D018020:Lithium Compounds; D049990:Membrane Transport Modulators; D015222:Sodium Channels; C469950:para protein, Drosophila
keywords: Drosophila; lithium; neurogenetics; seizure; voltage-gated sodium channel