ZFIN ID: ZDB-PUB-160203-5
Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2
Hoffman, E.J., Turner, K.J., Fernandez, J.M., Cifuentes, D., Ghosh, M., Ijaz, S., Jain, R.A., Kubo, F., Bill, B.R., Baier, H., Granato, M., Barresi, M.J., Wilson, S.W., Rihel, J., State, M.W., Giraldez, A.J.
Date: 2016
Source: Neuron   89(4): 725-33 (Journal)
Registered Authors: Baier, Herwig, Barresi, Michael J. F., Bill, Brent, Cifuentes, Daniel, Ghosh, Marcus, Giraldez, Antonio, Granato, Michael, Hoffman, Ellen, Jain, Roshan, Kubo, Fumi, Rihel, Jason, Wilson, Steve
Keywords: none
MeSH Terms:
  • 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
PubMed: 26833134 Full text @ Neuron
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.