Journal article
Glyoxalase 1 increases anxiety by reducing GABA(A) receptor agonist methylglyoxal
The Journal of clinical investigation, Vol.122(6), pp.2306-2315
06/01/2012
DOI: 10.1172/JCI61319
PMCID: PMC3366407
PMID: 22585572
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.
Details
- Title: Subtitle
- Glyoxalase 1 increases anxiety by reducing GABA(A) receptor agonist methylglyoxal
- Creators
- Margaret G Distler - University of ChicagoLeigh D Plant - Univ Chicago, Dept Pediat, Chicago, IL 60637 USAGreta Sokoloff - Univ Chicago, Dept Human Genet, Chicago, IL 60637 USAAndrew J Hawk - Univ Chicago, Dept Pathol, Chicago, IL 60637 USAIvy Aneas - Univ Chicago, Dept Human Genet, Chicago, IL 60637 USAGerald E Wuenschell - Beckman Res Inst City Hope, Div Mol Med, Duarte, CA USAJohn Termini - Beckman Res Inst City Hope, Div Mol Med, Duarte, CA USAStephen C Meredith - Univ Chicago, Dept Pathol, Chicago, IL 60637 USAMarcelo A Nobrega - Univ Chicago, Dept Human Genet, Chicago, IL 60637 USAAbraham A Palmer - Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.122(6), pp.2306-2315
- DOI
- 10.1172/JCI61319
- PMID
- 22585572
- PMCID
- PMC3366407
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Number of pages
- 10
- Grant note
- P60 DK020595 / University of Chicago Diabetes Research and Training Center; University of Chicago P60DK020595 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01HL088393 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01DA021336 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission R01MH079103 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) R01HG004428 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) R01MH079103; R01DA021336; T32GM07281; R01NS058505 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32GM007281 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01NS058505 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Language
- English
- Date published
- 06/01/2012
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984256839802771
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