title: 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.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Distler
authors.forename: Leigh D
authors.initials: LD
authors.lastname: Plant
authors.forename: Greta
authors.initials: G
authors.lastname: Sokoloff
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hawk
authors.forename: Ivy
authors.initials: I
authors.lastname: Aneas
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Wuenschell
authors.forename: John
authors.initials: J
authors.lastname: Termini
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Meredith
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Nobrega
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Palmer
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects; D058785:GABA-A Receptor Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D058785:GABA-A Receptor Agonists; D009419:Nerve Tissue Proteins; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase