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VGF function in depression and antidepressant efficacy

Molecular Psychiatry volume 23, pages 1632–1642 (2018)Cite this article

Abstract

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/−) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

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Acknowledgments

Supported in part by: NIH grants MH086499 (SRS), MH083496 (SRS), pilot grant on P50AT008661 (SRS; PI G.M. Pasinetti); MH090264 (SJR); Hope for Depression Research Foundation (SRS); BrightFocus Foundation (SRS); Brain and Behavior Research Foundation (SRS and CM); CM is a P&S Fund Investigator (Young Investigator Grant). CJ, W-JL, SJR and SRS designed the research; CJ, W-JL and MS performed the research; CJ, and W-JL analyzed the data; CAT, GT, CM, MLP, SJR, BL and EJN provided reagents/samples; CJ and SRS wrote the paper.

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Authors and Affiliations

  1. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    C Jiang, W-J Lin, M Sadahiro, B Labonté, C Menard, M L Pfau, E J Nestler, S J Russo & S R Salton

  2. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    C Jiang, M Sadahiro & M L Pfau

  3. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    C A Tamminga

  4. Department of Psychiatry, McGill University, Montreal, QC, Canada

    G Turecki

  5. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    E J Nestler, S J Russo & S R Salton

  6. Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    S R Salton

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  1. C Jiang
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Jiang, C., Lin, WJ., Sadahiro, M. et al. VGF function in depression and antidepressant efficacy. Mol Psychiatry 23, 1632–1642 (2018). https://doi.org/10.1038/mp.2017.233

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