title: Exaggerated Nighttime Sleep and Defective Sleep Homeostasis in a Drosophila Knock-In Model of Human Epilepsy.
abstract: Despite an established link between epilepsy and sleep behavior, it remains unclear how specific epileptogenic mutations affect sleep and subsequently influence seizure susceptibility. Recently, Sun et al. (2012) created a fly knock-in model of human generalized epilepsy with febrile seizures plus (GEFS+), a wide-spectrum disorder characterized by fever-associated seizing in childhood and lifelong affliction. GEFS+ flies carry a disease-causing mutation in their voltage-gated sodium channel (VGSC) gene and display semidominant heat-induced seizing, likely due to reduced GABAergic inhibitory activity at high temperature. Here, we show that at room temperature the GEFS+ mutation dominantly modifies sleep, with mutants exhibiting rapid sleep onset at dusk and increased nighttime sleep as compared to controls. These characteristics of GEFS+ sleep were observed regardless of sex, mating status, and genetic background. GEFS+ mutant sleep phenotypes were more resistant to pharmacologic reduction of GABA transmission by carbamazepine (CBZ) than controls, and were mitigated by reducing GABAA receptor expression specifically in wake-promoting pigment dispersing factor (PDF) neurons. These findings are consistent with increased GABAergic transmission to PDF neurons being mainly responsible for the enhanced nighttime sleep of GEFS+ mutants. Additionally, analyses under other light conditions suggested that the GEFS+ mutation led to reduced buffering of behavioral responses to light on and off stimuli, which contributed to characteristic GEFS+ sleep phenotypes. We further found that GEFS+ mutants had normal circadian rhythms in free-running dark conditions. Interestingly, the mutants lacked a homeostatic rebound following mechanical sleep deprivation, and whereas deprivation treatment increased heat-induced seizure susceptibility in control flies, it unexpectedly reduced seizure activity in GEFS+ mutants. Our study has revealed the sleep architecture of a Drosophila VGSC mutant that harbors a human GEFS+ mutation, and provided unique insight into the relationship between sleep and epilepsy.
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Petruccelli
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lansdon
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, United States of America; Department of Anesthesia, Carver College of Medicine, University of Iowa, Iowa City, IA, United States of America.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kitamoto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004827:Epilepsy / Q000209:etiology* / Q000503:physiopathology*; D004829:Epilepsy, Generalized / Q000209:etiology / Q000503:physiopathology; D005260:Female; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D017440:Photoperiod; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D003294:Seizures, Febrile / Q000209:etiology / Q000503:physiopathology; D012890:Sleep / Q000187:drug effects; D012892:Sleep Deprivation / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C082030:Rdl protein, Drosophila; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid