Methylglyoxal mildly impairs spatial memory and reduces expression of excitatory synaptic genes in the hippocampus of male mice.

Diabetes is associated with cognitive impairment and alterations in synaptic molecules; however, the factors within the diabetic milieu that drive these central changes remain unclear. Methylglyoxal (MG), a reactive dicarbonyl and major precursor of advanced glycation end products, accumulates under hyperglycemic and metabolically compromised conditions and is a candidate mediator of diabetic phenotypes. Here, we examined whether chronic MG exposure affects metabolism, behavior, and the expression of synaptic genes in the hippocampus and prefrontal cortex. Mice received MG in drinking water for 1 or 3 months, and then metabolic, behavioral, and biochemical analyses were performed. MG mildly impaired glucose clearance and induced insulin resistance, together with reduced adiposity in the 3-month intervention, indicating a disturbance of glucose and lipid metabolism. MG did not consistently affect anxiety-like behavior. In the Barnes maze test, MG mildly impaired spatial memory performance. In the hippocampus, MG selectively decreased the expression levels of the excitatory synaptic genes, whereas no gene was altered in the prefrontal cortex. These findings identify learning-associated excitatory synaptic genes as targets of chronic MG exposure and position MG as a candidate factor linking the diabetic metabolic state to hippocampal synaptic and cognitive alterations.