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.

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

“…Few studies have assessed the effects of MG in the central nervous system and particularly on degenerative diseases, dementia, anxiety, sleep disorders, and cerebrovascular diseases (Fig. ).…”

Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats

“…Interestingly, a role for Glo1 in two other behavioral domains that are often comorbid with alcoholism has also been demonstrated. The genetic and pharmacological manipulation of Glo1 also affects anxiety-like behavior (Distler et al, 2012;McMurray et al, 2016;Williams et al, 2009) and depression-related behavior (McMurray et al, 2017b). This raises the possibility that GLO1 inhibitors may be useful for the treatment of AUD and other common comorbid conditions.…”

Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation

“…Similar correlations between elevated methylglyoxal ( Beeri et al., 2011 ; Fleming et al., 2011 ), disruption of paranodal structures ( Sugiyama et al., 2002 ; Hinman et al., 2006 ), and calpain activation ( Nixon, 2003 ) exist in the setting of aging-related neurological dysfunction. Finally, methylglyoxal is implicated in other diseases and conditions such as pain (Griggs et al., 2016 , 2017a ; Brings et al., 2017 ; Liu et al., 2017 ; Wei et al., 2017 ), anxiety ( Distler and Palmer, 2012 ; Distler et al., 2012 ; McMurray et al., 2016 ), Alzheimer’s disease (Kuhla et al., 2005 , 2007 ), and sepsis ( Brenner et al., 2014 ; Schmoch et al., 2017 ). It is unknown whether nodal units are disrupted in these conditions.…”