Brain Angiopathy and Impaired Glucose Metabolism in Model Mice with Psychiatric-Related Phenotypes

Psychiatric disorders are associated with metabolic dysfunction, but it is unclear whether our current high-sugar diet contributes to pathogenesis. We demonstrate that a high-sucrose diet during adolescence induces behavioral phenotypes of psychiatric disease, such as hyperactivity, poor working memory, anxiety, and impaired sensory gating, in mice deficient for glyoxalase-1, an enzyme involved in detoxification of sucrose metabolites. The high-sucrose diet also induced advanced glycation end product accumulation in brain microcapillary endothelium, disrupted interneuron function and striatal dopamine release, and reduced brain glucose uptake. Aspirin protected against this angiopathy, enhanced brain glucose uptake, and prevented abnormal behavioral phenotypes. Brains from schizophrenia and bipolar disorder patients exhibited similar angiopathy. Psychiatric disorders are associated with microvascular brain damage, possibly due to variety of environmental stresses including metabolic stress.