BDNF Release and Signaling are Required for the Antidepressant Actions of GLYX-13

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 NMDA modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine 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, mutant mouse, and pharmacological approaches to test the role of BDNF-TrkB signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-mPFC infusion of an anti-BDNF neutralizing antibody 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 Ca(2+) 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.