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An affective disorder in zebrafish with mutation of the glucocorticoid receptor

Molecular Psychiatry volume 18, pages 681–691 (2013)Cite this article

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Abstract

Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium (‘novel tank’), mutant fish become immobile (‘freeze’), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants.

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Acknowledgements

We thank J Kitamoto and M Suzawa for technical assistance on some of our preliminary experiments; E Gahtan, NM Shah, R Carpenter, R Fletterick, R Fernald and M Dallman for advice and comments; S Hong and I Dawid for sending us the kohtalo mutant for complementation testing; G Rechavi for support of LZ, and members of the Baier lab for discussions.

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Author notes

  1. A Muto

    Present address: 7Current address: Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.,

  2. S H Meijsing

    Present address: 8Current address: Max Planck Institute for Molecular Genetics, Berlin, Germany.,

Authors and Affiliations

  1. Department of Physiology, Programs in Neuroscience, Genetics, and Developmental and Stem Cell Biology, University of California, San Francisco, CA, USA

    L Ziv, A Muto, P J Schoonheim & H Baier

  2. Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel

    L Ziv

  3. Institute of Biology, Leiden University, Leiden, The Netherlands

    P J Schoonheim & M J M Schaaf

  4. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

    S H Meijsing, H A Ingraham & K R Yamamoto

  5. Institute of Chemistry, Hebrew University of Jerusalem, Jerusalem, Israel

    D Strasser

  6. Department Genes, Circuits and Behavior, Max Planck Institute of Neurobiology, Martinsried, Germany

    H Baier

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Ziv, L., Muto, A., Schoonheim, P. et al. An affective disorder in zebrafish with mutation of the glucocorticoid receptor. Mol Psychiatry 18, 681–691 (2013). https://doi.org/10.1038/mp.2012.64

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