RRC ID 49685
Author Hoffman EJ, Turner KJ, Fernandez JM, Cifuentes D, Ghosh M, Ijaz S, Jain RA, Kubo F, Bill BR, Baier H, Granato M, Barresi MJ, Wilson SW, Rihel J, State MW, Giraldez AJ.
Title Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.
Journal Neuron
Abstract Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.
Volume 89(4)
Pages 725-33
Published 2016-2-17
DOI 10.1016/j.neuron.2015.12.039
PII S0896-6273(15)01167-8
PMID 26833134
PMC PMC4766582
MeSH Animals Animals, Genetically Modified Autistic Disorder / drug therapy* Autistic Disorder / genetics Disease Models, Animal Estrogens / pharmacology* Estrogens / therapeutic use Gene Expression Regulation / drug effects* Gene Expression Regulation / genetics* Genistein / pharmacology Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Humans Larva Luminescent Proteins / genetics Luminescent Proteins / metabolism Membrane Proteins / genetics* Motor Activity / drug effects Motor Activity / genetics Mutation / genetics* Nerve Tissue Proteins / genetics* Phenotype Phytoestrogens / pharmacology Psychotropic Drugs / pharmacology Psychotropic Drugs / therapeutic use Seizures / drug therapy Seizures / genetics Sleep-Wake Transition Disorders / drug therapy Sleep-Wake Transition Disorders / genetics Vesicular Glutamate Transport Protein 2 / genetics Vesicular Glutamate Transport Protein 2 / metabolism Zebrafish
IF 14.415
Times Cited 59
Zebrafish Tg(vglut2a:loxP-DsRed-loxP-GFP)