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Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in mice and humans

Molecular Psychiatry volume 18, pages 957–958 (2013)Cite this article

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Major depression, a common mental illness affecting millions of people worldwide, is one of the leading causes of morbidity and has a significant economic cost. Although the mechanisms of action are not well understood, antidepressants, including serotonin-selective reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have been used for the treatment of depression, anxiety and other psychiatric disorders.1 Here we identified a Wnt signaling inhibitor,2 secreted frizzled-related protein 3 (sFRP3), as a molecular target of antidepressant treatments in rodent models, and revealed the significant association of three single-nucleotide polymorphisms (SNPs) in FRZB (the sFRP3 human ortholog) with early antidepressant responses in a clinical cohort.

The function of sFRP3 in the nervous system is unknown. To test the possibility that sFRP3 downregulation mediates antidepressant action, we subjected sFRP3 knockout (KO) mice to a panel of behavioral analyses (see Supplementary Information). sFRP3 KO mice exhibited apparently normal development and no differences in locomotor activity and anxiety-like behaviors in the open-field, elevated-plus maze and light–dark tests compared to wild-type (WT) littermates (Supplementary Figures 1a–g). In tail-suspension and forced-swimming tests, which are reliable predictors of antidepressant potential,5 vehicle-treated adult KO or heterozygous (HET) mice showed significantly reduced levels of immobility compared to WT animals (Figures 1c and d and Supplementary Figures 1h and i). Notably, fluoxetine treatment did not cause a further decrease in immobility in KO and HET mice (Figures 1c and d), indicating that sFRP3 downregulation alone is sufficient to induce antidepression-like behavioral responses.

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Authors and Affiliations

  1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M-H Jang, Y Kitabatake, E Kang, H Jun, K M Christian, H Song & G-I Ming

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M-H Jang, Y Kitabatake, H Jun, M V Pletnikov, K M Christian, H Song & G-I Ming

  3. Department of Neurologic Surgery, Department of Biochemistry and Molecular Biology, Mayo College of Medicine, Rochester, MN, USA

    M-H Jang

  4. Department of Pediatrics, Osaka University School of Medicine, Osaka, Japan

    Y Kitabatake

  5. Pre-doctoral Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    E Kang & H Song

  6. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M V Pletnikov

  7. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M V Pletnikov, H Song & G-I Ming

  8. Department of Psychiatry, Columbia University, New York, NY, USA

    R Hen

  9. The New York State Psychiatric Institute, New York, NY, USA

    R Hen

  10. Max Planck Institute of Psychiatry, Munich, Germany

    S Lucae & E B Binder

  11. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    E B Binder

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  1. M-H Jang
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  8. S Lucae
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  11. G-I Ming
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Corresponding authors

Correspondence to E B Binder, H Song or G-I Ming.

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Competing interests

Dr Binder receives grant support from NIMH, Behrens-Weise Foundation and the Seventh Framework Program from the European Commission. Dr Binder is also a coinventor on the following patents: FKBP5: a novel target for antidepressant therapy (International publication number: WO 2005/054500) and Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments (International application number: PCT/EP2005/005194). All other auhors declare no conflicts of interest.

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Jang, MH., Kitabatake, Y., Kang, E. et al. Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in mice and humans. Mol Psychiatry 18, 957–958 (2013). https://doi.org/10.1038/mp.2012.158

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