Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal
Margaret G. Distler, … , Marcelo A. Nobrega, Abraham A. Palmer
Margaret G. Distler, … , Marcelo A. Nobrega, Abraham A. Palmer
Published May 15, 2012
Citation Information: J Clin Invest. 2012;122(6):2306-2315. https://doi.org/10.1172/JCI61319.
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Research Article Neuroscience

Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal

Abstract

Glyoxalase 1 (Glo1) expression has previously been associated with anxiety in mice; however, its role in anxiety is controversial, and the underlying mechanism is unknown. Here, we demonstrate that GLO1 increases anxiety by reducing levels of methylglyoxal (MG), a GABAA receptor agonist. Mice overexpressing Glo1 on a Tg bacterial artificial chromosome displayed increased anxiety-like behavior and reduced brain MG concentrations. Treatment with low doses of MG reduced anxiety-like behavior, while higher doses caused locomotor depression, ataxia, and hypothermia, which are characteristic effects of GABAA receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated GABAA receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing GABAA receptor activation. More broadly, our findings potentially link metabolic state, neuronal inhibitory tone, and behavior. Finally, we demonstrated that pharmacological inhibition of GLO1 reduced anxiety, suggesting that GLO1 is a possible target for the treatment of anxiety disorders.

Authors

Margaret G. Distler, Leigh D. Plant, Greta Sokoloff, Andrew J. Hawk, Ivy Aneas, Gerald E. Wuenschell, John Termini, Stephen C. Meredith, Marcelo A. Nobrega, Abraham A. Palmer

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Figure 6

MG is a GABAA receptor agonist in HNs.

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MG is a GABAA receptor agonist in HNs. (A) Both GABA and MG evoked con...
(A) Both GABA and MG evoked concentration-dependent inward currents in HNs. The EC50 of currents evoked by MG was 9.5 ± 0.9 μM, with a Hill coefficient of 1.05. The relative amplitude of the currents was normalized to that cell’s response to 100 μM MG. Currents evoked by 100 μM GABA were reduced by coapplication of MG in a concentration-dependent manner. Scale bars: 1 nA, 10 s. Mean data for competition experiments are shown normalized to the current evoked by 100 μM GABA in each cell. (B) Currents evoked by 10 μM MG or GABA were augmented by coapplication of 500 nM diazepam, midazolam, or zolpidem. Scale bars: 1 nA, 10 s. Mean data are plotted as histograms. The bar above each trace shows the duration of drug application. Data are mean ± SEM for 8–10 cells per condition.