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BDNF release and signaling are required for the antidepressant actions of GLYX-13

Molecular Psychiatry volume 23, pages 2007–2017 (2018)Cite this article

Abstract

Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-d-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized. Here we use a combination of neutralizing antibody (nAb), mutant mouse and pharmacological approaches to test the role of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TrkB) signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex (intra-mPFC) infusion of an anti-BDNF nAb or in mice with a knock-in of the BDNF Val66Met allele, which blocks the processing and activity-dependent release of BDNF. We also demonstrate that pharmacological inhibitors of BDNF-TrkB signaling or of l-type voltage-dependent Ca2+ channels (VDCCs) block the antidepressant behavioral actions of GLYX-13. Finally, we examined the role of the Rho GTPase proteins by injecting a selective inhibitor into the mPFC and found that activation of Rac1 but not RhoA is involved in the antidepressant effects of GLYX-13. Together, these findings indicate that enhanced release of BDNF through exocytosis caused by activation of VDCCs and subsequent TrkB-Rac1 signaling is required for the rapid and sustained antidepressant effects of GLYX-13.

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Acknowledgments

This study was supported by NIMH grants MH045481 (RSD), MH093897 (RSD), the state of Connecticut, Sumitomo Dainippon Pharma (TK), and a research grant from Allergan. RSD has consulted and/or received research support from Naurex, Allergan, Lilly, Forest, Johnson & Johnson, Taisho, Sunovion and Navitor.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    T Kato, M V Fogaça, S Deyama, X-Y Li, K Fukumoto & R S Duman

  2. Drug Development Research Laboratories, Sumitomo Dainippon Pharma, New Haven, CT, USA

    T Kato

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Correspondence to R S Duman.

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Kato, T., Fogaça, M.V., Deyama, S. et al. BDNF release and signaling are required for the antidepressant actions of GLYX-13. Mol Psychiatry 23, 2007–2017 (2018). https://doi.org/10.1038/mp.2017.220

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