PgmNr Z640: Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

Authors:
Ellen J. Hoffman 1 ; Katherine J. Turner 2 ; Joseph M. Fernandez 1 ; Daniel Cifuentes 1,3 ; Marcus Ghosh 2 ; Sundas Ijaz 1 ; Roshan A. Jain 4,5 ; Fumi Kubo 6 ; Brent R. Bill 7,8 ; Herwig Baier 6 ; Michael Granato 4 ; Michael J. F. Barresi 9 ; Stephen W. Wilson 2 ; Jason Rihel 2 ; Matthew W. State 1,10 ; Antonio J. Giraldez 1


Institutes
1) Yale University, New Haven, CT; 2) University College London, London, UK; 3) Boston University School of Medicine, Boston, MA; 4) University of Pennsylvania, Philadelphia, PA; 5) Haverford College, Haverford, PA; 6) Max Planck Institute of Neurobiology, Martinsried, Germany; 7) University of California, Los Angeles, CA; 8) The University of Texas at Tyler, Tyler, TX; 9) Smith College, Northampton, MA; 10) University of California, San Francisco, San Francisco, CA.


Abstract:

Autism spectrum disorders (ASD) 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 ASD remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASD. We generated zebrafish mutants of cntnap2 and conducted pharmacological screens to identify phenotypic suppressors. We found that zebrafish cntnap2 mutants display GABAergic deficits particularly in the forebrain and sensitivity to drug-induced seizures. High-throughput behavioral profiling identified nighttime hyperactivity in cntnap2 mutants, while pharmacological testing revealed dysregulation of GABAergic and glutamatergic systems. Finally, we found that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and showed 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. We are utilizing pharmaco-behavioral profiling of zebrafish mutants of multiple ASD risk genes to identify relevant biological pathways and potential pharmacological candidates for further evaluation.



ZFIN Genetics Index
1. cntnap2a
2. cntnap2b