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Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

ABSTRACT: Methylglyoxal (MG) is a reactive alpha-dicarbonyl by-product of glycolysis. Several bio-defense systems to detoxify the highly toxic MG are equipped in our body, including an enzymatic system by glyoxalase (GLO) 1 and GLO2 and a scavenge system by vitamin B6 (VB6). We have reported that some population of patients with schizophrenia shows impairment of the MG detoxification systems. Although we have evidences showing a link between impairment of MG detoxification systems and development of schizophrenia, the molecular mechanism to connect them remains poorly understood. Here, we generated a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice with VB6-lacking diets (KO/VB6(-)), and evaluate effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice showed the accumulation of MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits, such as social deficits, cognitive impairment, a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-seq and weighted gene correlation network analysis (WGCNA). Finally, we actually demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.

ORGANISM(S): Mus musculus

PROVIDER: GSE149585 | GEO | 2021/07/20

REPOSITORIES: GEO

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Project description:Background: Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown. Objective: We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Methods: Fischer344/Jcl male rats aged 21–39 days were fed low-iron diets (0.35 mg/kg iron; ID group) or standard AIN-93 G diets (3.5 mg/kg iron; control group). The locomotor activity of male offspring was evaluated by the open field and elevated plus maze tests at ages 8 and 12 weeks. Monoamine concentrations in the PFC, NAcc, caudate-putamen, ventral midbrain, dorsal midbrain, and pons were analyzed. Comprehensive gene expression analysis was performed in the PFC and NAcc at age 13 weeks. Finally, we investigated synaptic density in the PFC and NAcc by synaptophysin immunostaining. Results: Behavioral tests revealed significant interactions between age and iron consumption for the total distance traveled and the distance traveled in the peripheral area (p < 0.05), indicating that ID during the juvenile period affected hyperactivity and that this persisted to adulthood. At age 13 weeks, the ID group had increased levels of both dopamine and the metabolites of dopamine and serotonin in the NAcc. Comprehensive gene expression analysis and immunostaining showed decreased Reelin gene expression (adjusted p < 0.01) and significantly increased spine density in the NAcc in the ID group compared with the control group (p < 0.01). Conclusions: ID during the postweaning juvenile period led to long-term hyperactivity, monoamine disturbance in the brain, and downregulation of Reelin expression in the NAcc despite complete iron repletion. Epigenetic modification of Reelin genes may be involved in synaptic plasticity in the NAcc.

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Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

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