Phenylketonuria-related cognitive dysfunction and its mechanism in a BTBR-Pahenu2 mouse model

Objective: Phenylketonuria is the most common inherited aminoacidopathy, characterized by elevated level of phenylalanine in the plasma and cerebrospinal fluid of patients, which eventually leads to cognitive dysfunction. However, the underlying mechanisms are not clear yet. In the present study, we aimed to examine the spatial cognitive function in the phenylketonuria mouse model and explore the underlying molecular mechanisms. Methods: We chose BTBR-Pahenu2 mouse, the most classical model of phenylketonuria, for our study of cognitive function. Genotyping was performed by blood phenylalanine measurement and genetic methods. We examined the spatial cognitive function in eight-arm maze test by comparing the performance of wild type and homozygous BTBR-Pahenu2 mice. Subsequently we investigated the expression and phosphorylation of Akt/GSK-3β/β-Catenin pathway in the prefrontal cortex and CA1 region of the hippocampus by western blot. Results: Homozygous BTBR-Pahenu2 mice showed impaired spatial cognitive function in the eight-arm maze test. Subsequent experiments confirmed that the phosphorylation of Akt and GSK-3β was significantly lower in the prefrontal cortex and CA1 of the homozygous BTBR-Pahenu2 mice, together with a decrease of β-catenin expression. There was no change in the expression of Akt and GSK-3β. Conclusions: The activity of the Akt/GSK-3β/β-Catenin pathway was inhibited in the prefrontal cortex and CA1 of the homozygous BTBR-Pahenu2 mice. Considering the important role of Akt/GSK-3β/β-Catenin pathway in cognition, these changes may be critical pathological mechanisms underlying cognitive dysfunction in phenylketonuria. These findings provide direct evidence that Akt/GSK-3β/β-Catenin pathway is involved in the brain injury of phenylketonuria.