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 GABA A 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 GABA A receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated GABA A receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing GABA A 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.

Modulatory effect of diphenyl diselenide in Carioca High- and Low-conditioned Freezing rats

“…However, several contradictory reports have also been published. To further explore the mechanism of anxiety regulation, Hambsch et al (2010) and Distler et al (2012) reported that methylglyoxal (MG), the substrate for GLO1, is responsible for the regulation of anxiety. The neuroendocrine, neurochemical, and neurogenetic profiles of the CHF and CLF lines have not yet been explored.…”

Genetic analysis of the glyoxalase system in schizophrenia

“…The broad spatial and temporal expression patterns highlight the crucial importance of the glyoxalase system for biological function. Recent studies revealed alterations in GLO1 expression in neuropsychiatric disorders for mood (Fujimoto et al, 2008), anxiety (Distler et al, 2012;Hovatta et al, 2005;Kromer et al, 2005;Politi et al, 2006) and schizophrenia (Itokawa et al, 2014), but their expression levels have not been examined in postmortem brains. Our analysis, however, did not observe any differences in expression levels of both genes between schizophrenia and controls in BA46 and the hippocampal CA1 subfield.…”

Copy number variation of glyoxalase I

“…In attempts to link Glo1 metabolically to dysfunctional brain metabolism, MG concentration in brain tissue of mice has been estimated at approximately 170-360 μM [27] and 5 μM MG [28], which appear to be overestimates compared with those of 0.3 and 1.5 μM brain stem/midbrain and cortex when peroxidase and other interferences in the MG assay are blocked [29]. MG was found to agonize the GABA A (γ -aminobutyric acid A) receptor in primary cerebellar granule neurons with a median effective concentration EC 50 of 10.5 μM.…”

“…MG was found to agonize the GABA A (γ -aminobutyric acid A) receptor in primary cerebellar granule neurons with a median effective concentration EC 50 of 10.5 μM. MG agonism at the GABA A receptor was proposed as a mediator of sedation to explain increased Glo1 CNV with an anxiety phenotype [28]. MG concentration in mouse brain tissue is approximately 7-fold lower than this [29] and only approached the EC 50 value with dosing of 300 mg of MG/kg of body mass [28], similar to doses that have previously produced acute toxicity [30].…”

“…MG agonism at the GABA A receptor was proposed as a mediator of sedation to explain increased Glo1 CNV with an anxiety phenotype [28]. MG concentration in mouse brain tissue is approximately 7-fold lower than this [29] and only approached the EC 50 value with dosing of 300 mg of MG/kg of body mass [28], similar to doses that have previously produced acute toxicity [30]. This and previous links of an anxiety phenotype with both increased and decreased Glo1 expression [24,25] is an indication that further investigation is required.…”