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

• DOI: 10.1038/mp.2017.220
• Publication Date: 2017-12-05T09:01:12Z
• Authors: T Kato; M V Fogaça; S Deyama; X-Y Li; K Fukumoto; R S Duman
• Keywords: Male; 0301 basic medicine; Membrane Glycoproteins; N-Methylaspartate; Depression; Brain-Derived Neurotrophic Factor; Prefrontal Cortex; Receptors, N-Methyl-D-Aspartate; Article; Antidepressive Agents; Rats; 3. Good health; Mice, Inbred C57BL; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Animals; Receptor, trkB; Ketamine; Oligopeptides; Signal Transduction

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.