title: Neuronal overexpression of Glo1 or amygdalar microinjection of methylglyoxal is sufficient to regulate anxiety-like behavior in mice.
abstract: GLO1 (Glyoxalase1) is a ubiquitous cellular enzyme that detoxifies methylglyoxal (MG), which is a byproduct of glycolysis. Previously, we showed that ubiquitous overexpression of Glo1 reduced concentrations of MG and increased anxiety-like behavior, whereas systemic injection of MG reduced anxiety-like behavior. We further showed that MG is a competitive partial agonist at GABA-A receptors. Based on those data we hypothesized that modulation of GABAergic signaling by MG underlies Glo1 and MG's effects on anxiety-like behavior. As previous studies used ubiquitous overexpression, we sought to determine whether neuronal Glo1 overexpression was sufficient to increase anxiety-like behavior. We generated ROSA26 knock-in mice with a floxed-stop codon upstream from human Glo1 (FLOXGlo1KI) and bred them with mice expressing CRE recombinase under the direction of the Synapsin 1 promoter (Syn-CRE) to limit overexpression of Glo1 specifically to neurons. Furthermore, since previous administration of MG had been systemic, we sought to determine if direct microinjection of MG into the basolateral amygdala (BLA) was sufficient to reduce anxiety-like behavior. Thus, we performed bilateral microinjections of saline, MG (12μM or 24μM), or the positive control midazolam (4mM) directly into the BLA. FLOXGlo1KIxSyn-CRE mice showed significantly increased anxiety-like behavior compared to their FLOXGLO1xWT littermates. In addition, bilateral microinjection of MG and midazolam significantly decreased anxiety-like behavior compared to saline treated mice. These studies suggest that anatomically specific manipulations of Glo1 and MG are sufficient to induce changes in anxiety-like behavior.
authors.affiliation: Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: K M J
authors.initials: KM
authors.lastname: McMurray
authors.affiliation: Diabetes Research Center, Department of Medicine and Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.affiliation: Diabetes Research Center, Department of Medicine and Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Brownlee
authors.affiliation: Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: aap@ucsd.edu.
authors.forename: A A
authors.initials: AA
authors.lastname: Palmer
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001008:Anxiety Disorders / Q000188:drug therapy / Q000378:metabolism*; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage; D055879:Gene Knock-In Techniques; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008845:Microinjections; D008874:Midazolam / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011765:Pyruvaldehyde / Q000008:administration & dosage*; D011963:Receptors, GABA-A / Q000378:metabolism; D016704:Synapsins / Q000235:genetics / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D016704:Synapsins; D011765:Pyruvaldehyde; C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase; D008874:Midazolam
keywords: Anxiety; GLO1; Glyoxalase 1; MG; Methylglyoxal