Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

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. Overall design: Glo1 KO and wild-type mice were fed with a vitamin B6 (VB6)-lacking diet containing 5 micro g/100 g VB6 pellets from 8 to 12 weeks of age, while control mice in normal VB6 condition were fed with a normal diet, with 1.4 mg/100 g VB6 pellets. As the result, we have four groups: WT/VB6(+), WT/VB6(-), KO/VB6(+) and KO/VB6(-). Each group contains 5 mice. RNA-seq were consucted using RNAs extracted from prefrontal cortex, striatum and hippocampus of these mice.