Novel mechanisms mediating the rapid antidepressant actions of glyoxylase 1 inhibitors

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PROJECT SUMMARY Depression is the leading cause of disability worldwide. The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is the only agent approved for clinical use that induces antidepressant effects within hours to days. However, ketamine treatment is not effective in all patients, and induces problematic side effects. Novel rapid-acting antidepressant agents are greatly needed. We recently found that glyoxylase 1 (GLO1) inhibitors induce rapid-onset antidepressant effects in mice. GLO1 is a ubiquitous cellular enzyme that detoxifies methylglyoxal (MG), a non-enzymatic byproduct of glycolysis. Thus, GLO1 inhibitor treatment increases physiological levels of MG. MG is a competitive partial agonist at GABA-A receptors, and also directly activate tropomyosin receptor kinase B (TrkB), the receptor for brain derived neurotrophic factor (BDNF). Ketamine, and agents inducing rapid-onset antidepressant effects in rodents, trigger activity- dependent BDNF release leading to TrkB activation; this action is required for their rapid-onset antidepressant effects. This proposal aims to identify the molecular and circuit mechanisms that underlie GLO1 inhibitor- induced rapid onset antidepressant effects. We found that GLO1 inhibitor treatment induces antidepressant effects within 24 hours through mechanisms that are largely distinct from those of ketamine. For example, ketamine and other rapid-acting agents induce activation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which triggers activity-dependent BDNF release and cortical γ oscillations. Surprisingly, we found that GLO1 inhibitor treatment does not induce γ oscillations, and thus likely does not induce AMPA activation or activity-dependent BDNF release. In Aim 1, we will test the hypothesis that GLO1 inhibitor treatment leads to TrkB activation by increasing levels of MG, thus “substituting” for BDNF release. We predict that mice carrying the Val66Met mutation in BDNF, which prevents activity-dependent BDNF release, will show rapid-onset antidepressant responses to GLO1 inhibitors, but not ketamine. We will also test the hypothesis that activation of TrkB receptors within the mPFC is sufficient for GLO1-inhibitor-mediated rapid antidepressant effects. Overactivity of the lateral habenula (LHb) produces depression-like behaviors, and reducing this overactivity has antidepressant effects. Our calcium imaging findings show that application of either MG or ketamine to LHb slices from congenitally helpless rats reduces LHb neuronal overactivity. While ketamine mediates this effect by blocking NMDARs and low-voltage-sensitive T-type calcium channels, we predict that GLO1 inhibitors produce this effect by activating GABA-ARs via MG. In Aim 2, we will test the hypothesis that activation of LHb GABA-ARs is sufficient to mediate GLO1-mediated rapid-onset antidepressant effects. Lastly, we will use multispectral photometry to test the hypothesis that GLO1 inhibitor-mediated inhibition of an mPFC- LHb projection is sufficient to induce rapid-onset antidepressant effects. Identifying novel mechanisms of rapid- onset antidepressant effects is essential for developing new therapeutics.