Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice

Hovatta, Iiris; Tennant, Richard S.; Helton, Robert; Marr, Robert A.; Singer, Oded; Redwine, Jeffrey M.; Ellison, Julie A.; Schadt, Eric E.; Verma, Inder M.; Lockhart, David J.; Barlow, Carrolee

doi:10.1038/nature04250

Cited by 427 publications

(397 citation statements)

References 25 publications

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“…Recently, GSSGrd has been proposed as a specific protein involved in anxiety response in mouse models (Hovatta et al, 2005). We described altered GSSGrd activity in the brain from the Fmr1-KO mice, linking this finding to altered anxiety responses in the fragile X mouse.…”

Section: Discussionmentioning

confidence: 64%

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Diego-Otero¹,

Romero-Zerbo²,

Bekay

et al. 2008

Neuropsychopharmacol

120

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Fragile X syndrome is the most common genetic cause of mental disability. The mechanisms underlying the pathogenesis remain unclear and specific treatments are still under development. Previous studies have proposed an abnormal hypothalamic-pituitary-adrenal axis and high cortisol levels are demonstrated in the fragile X patients. Additionally, we have previously described that NADPH-oxidase activation leads to oxidative stress in the brain, representing a pathological mechanism in the fragile X mouse model. Fmr1-knockout mice develop an altered free radical production, abnormal glutathione homeostasis, high lipid and protein oxidation, accompanied by stressdependent behavioral abnormalities and pathological changes in the first months of postnatal life. Chronic pharmacological treatment with a-tocopherol reversed pathophysiological hallmarks including free radical overproduction, oxidative stress, Rac1 and a-PKC activation, macroorchidism, and also behavior and learning deficits. The restoration of the oxidative status in the fragile X mouse emerges as a new and promising approach for further therapeutic research in fragile X syndrome.

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Section: Discussionmentioning

confidence: 64%

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Diego-Otero¹,

Romero-Zerbo²,

Bekay

et al. 2008

Neuropsychopharmacol

120

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“…69,70 Other genetic factors associated with glycolytic and oxidative metabolism have been linked to anxiety in humans 71 and mice. 72 If further studies demonstrate an association between trait vulnerability to PD and elevated lactate responses, then understanding the metabolic mechanism of this association will be an important priority.…”

Section: Discussionmentioning

confidence: 99%

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

et al. 2008

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Converging evidence suggests that patients with panic disorder have a metabolic disturbance that may influence the regulation of arousal systems and confer vulnerability to 'spontaneous' panic attacks. The consistent finding of elevated brain lactate responses to various metabolic challenges in panic disorder appears to support this model, although the mechanism of this effect is not understood. Several mechanisms have been proposed to account for elevated brain lactate responses in panic disorder, including (1) brain hypoxia due to excessive cerebral vasoconstriction, and (2) a metabolic disturbance affecting lactate metabolism. Recent studies have shown that neural activation (for example, sensory stimulation) causes local lactate accumulation in the presence of increased oxygen availability. The current study used proton magnetic resonance spectroscopic measures of visual cortex lactate changes during visual stimulation in 15 untreated patients with panic disorder and 15 matched volunteers to critically test these two proposed mechanisms of elevated brain lactate responses in panic disorder. Visual cortex lactate/N-acetylaspartate increased during visual stimulation in both groups. The increase was significantly greater in the panic patients than in the comparison group. There were no group differences in end-tidal pCO 2 . The finding that visual stimulation leads to significantly greater visual cortex lactate responses in panic patients is not predicted by the hypoxia model. These results suggest that a metabolic disturbance affecting the production or clearance of lactate is the cause of the elevated brain lactate responses consistently observed in panic disorder and provide further support for metabolic models of vulnerability to this illness.

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“…This is exemplified experimentally by PrP expression where transgenic mice overexpressing mouse PrP have a very short incubation time relative to wild-type mice and conversely, hemizygous mice have an extended incubation time (21,22). The principle of correlating endogenous expression levels with phenotype has also been applied successfully to mouse models of anxiety (26).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Grizenkova

Akhtar

Hummerich

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

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Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice

Cited by 427 publications

References 25 publications

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

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