Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2

Authors

Ellen J. Hoffman, Yale Child Study Center
Katherine J. Turner, University College London
Joseph M. Fernandez, Yale Child Study Center
Daniel Cifuentes, Yale School of Medicine
Marcus Ghosh, University College London
Sundas Ijaz, Yale Child Study Center
Roshan A. Jain, University of Pennsylvania Perelman School of Medicine
Fumi Kubo, Max Planck Institute of Neurobiology
Brent R. Bill, Jane & Terry Semel Institute for Neuroscience & Human Behavior
Herwig Baier, Max Planck Institute of Neurobiology
Michael Granato, University of Pennsylvania Perelman School of Medicine
Michael J.F. Barresi, Smith CollegeFollow
Stephen W. Wilson, University College London
Jason Rihel, University College London
Matthew W. State, Yale Child Study Center
Antonio J. Giraldez, Yale School of Medicine

Document Type

Article

Publication Date

2-17-2016

Publication Title

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. Hoffman et al. use zebrafish mutants of the autism risk gene Contactin Associated Protein-like 2 (CNTNAP2) to conduct high-throughput quantitative behavioral profiling and pharmacological screening. This approach reveals dysregulation of GABAergic and glutamatergic systems in mutants and identifies estrogenic compounds as suppressors of the mutant behavioral phenotype.

Volume

89

Issue

4

First Page

725

Last Page

733

DOI

10.1016/j.neuron.2015.12.039

ISSN

08966273

Rights

©2016 Elsevier Inc

Comments

Archived as published. Open access article.

Recommended Citation

Hoffman, Ellen J.; Turner, Katherine J.; Fernandez, Joseph M.; Cifuentes, Daniel; Ghosh, Marcus; Ijaz, Sundas; Jain, Roshan A.; Kubo, Fumi; Bill, Brent R.; Baier, Herwig; Granato, Michael; Barresi, Michael J.F.; Wilson, Stephen W.; Rihel, Jason; State, Matthew W.; and Giraldez, Antonio J., "Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2" (2016). Biological Sciences: Faculty Publications, Smith College, Northampton, MA.
https://scholarworks.smith.edu/bio_facpubs/197