PUBLICATION
Behavioral Comorbidities and Drug Treatments in a Zebrafish scn1lab Model of Dravet Syndrome.
- Authors
- Grone, B.P., Qu, T., Baraban, S.C.
- ID
- ZDB-PUB-170817-5
- Date
- 2017
- Source
- eNeuro 4(4): (Journal)
- Registered Authors
- Baraban, Scott, Grone, Brian
- Keywords
- Dravet syndrome, anxiety, epilepsy, sleep, sodium channels, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Anticonvulsants/therapeutic use*
- Cell Count
- Circadian Rhythm/genetics
- Cognitive Behavioral Therapy/methods*
- Disease Models, Animal
- Epilepsies, Myoclonic*/drug therapy
- Epilepsies, Myoclonic*/genetics
- Epilepsies, Myoclonic*/rehabilitation
- Exploratory Behavior/drug effects
- Female
- Genotype
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Interneurons/metabolism
- Interneurons/pathology
- Larva
- Locomotion/drug effects
- Male
- Mutation/genetics*
- NAV1.1 Voltage-Gated Sodium Channel/genetics*
- NAV1.1 Voltage-Gated Sodium Channel/metabolism
- Sleep Wake Disorders/etiology
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 28812061 Full text @ eNeuro
Citation
Grone, B.P., Qu, T., Baraban, S.C. (2017) Behavioral Comorbidities and Drug Treatments in a Zebrafish scn1lab Model of Dravet Syndrome.. eNeuro. 4(4).
Abstract
Loss-of-function mutations in SCN1A cause Dravet syndrome (DS), a catastrophic childhood epilepsy in which patients experience comorbid behavioral conditions, including movement disorders, sleep abnormalities, anxiety, and intellectual disability. To study the functional consequences of voltage-gated sodium channel mutations, we use zebrafish with a loss-of-function mutation in scn1lab, a zebrafish homolog of human SCN1A. Homozygous scn1labs552/s552 mutants exhibit early-life seizures, metabolic deficits, and early death. Here, we developed in vivo assays using scn1labs552 mutants between 3 and 6 d postfertilization (dpf). To evaluate sleep disturbances, we monitored larvae for 24 h with locomotion tracking software. Locomotor activity during dark (night phase) was significantly higher in mutants than in controls. Among anticonvulsant drugs, clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved at night for scn1labs552 mutant larvae. To monitor exploratory behavior in an open field, we tracked larvae in a novel arena. Mutant larvae exhibited impaired exploratory behavior, with increased time spent near the edge of the arena and decreased mobility, suggesting greater anxiety. Both clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved and increased time spent in the center of the arena. Counting inhibitory neurons in vivo revealed no differences between scn1labs552 mutants and siblings. Taken together, our results demonstrate conserved features of sleep, anxiety, and movement disorders in scn1lab mutant zebrafish, and provide evidence that a zebrafish model allows effective tests of treatments for behavioral comorbidities associated with DS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping