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Neuron. 2016 Feb 17;89(4):725-33. doi: 10.1016/j.neuron.2015.12.039. Epub 2016 Jan 28.

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

Author information

1
Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
2
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
3
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
4
Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Biology, Haverford College, Haverford, PA 19041, USA.
5
Department Genes - Circuits - Behavior, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
6
Center for Autism Research and Treatment, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biology, The University of Texas at Tyler, Tyler, TX 75799, USA.
7
Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
8
Department of Biological Sciences, Smith College, Northampton, MA 01063, USA.
9
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: j.rihel@ucl.ac.uk.
10
Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.state@ucsf.edu.
11
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: antonio.giraldez@yale.edu.

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.

PMID:
26833134
PMCID:
PMC4766582
DOI:
10.1016/j.neuron.2015.12.039
[Indexed for MEDLINE]
Free PMC Article

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