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 5

MG is a GABAA receptor agonist in CGNs.

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MG is a GABAA receptor agonist in CGNs. (A) CGNs are depolarized by MG...
(A) CGNs are depolarized by MG (white circles) or GABA (black circles) (EC50, 10.5 ± 0.5 μM MG; Hill coefficient, 1.17). The relative amplitude of depolarization is shown normalized to the response of each cell to 100 μM MG. (B) MG evokes inward currents in a concentration-dependent manner (EC50, 12 ± 0.7 μM; Hill coefficient, 1.13). The amplitude of currents is shown normalized to the peak response of each cell (I/Imax). (C) Depolarization evoked by 10 μM MG (left) or GABA (middle) was blocked by 10 μM SR. Mean data are plotted as a histogram (right). (D) Inward currents evoked by 10 μM MG (left) or GABA (middle) were also blocked by 10 μM SR. Mean data are plotted as a histogram (right). (E) Currents evoked by 100 μM GABA were reduced by coapplication of MG (left). Scale bars: 200 pA/pF, 25 s. Mean data are normalized to the current evoked by 100 μM GABA in each cell (right). (F) Currents observed approximately 40 seconds after the application of 10 μM MG to the inside of macropatches excised from CGNs were blocked when 10 μM SR was included in the pipette. Application of 10 μM GABA to the inside of macropatches did not evoke a current. Mean data are plotted as a histogram. The bar above each trace shows the duration of drug application. Data are mean ± SEM. n = 6–12 cells or macropatches per condition.