# Phenylketonuria Alters the Prefrontal Cortex Genome-Wide Expression Profile Regardless of the Mouse Genetic Background

## TL;DR

This study shows that phenylketonuria causes similar changes in the prefrontal cortex of mice, regardless of their genetic background, leading to cognitive issues.

## Contribution

The study reveals shared molecular and cognitive effects of phenylketonuria across different mouse strains.

## Key findings

- The enu2 mutation upregulates aminoacyl-tRNA synthetases and translation initiation factors in the prefrontal cortex.
- Gene programs related to myelination are downregulated in both mouse strains with the enu2 mutation.
- C57enu2− mice show a new working memory impairment under high information load.

## Abstract

Mouse models of genetic diseases are important research tools. However, the genetic background of the mouse strain can significantly influence how a genetic mutation is expressed. Studies on preclinical models of phenylketonuria (PKU), an inherited metabolic disorder, have used two strains, BTBR and C57Bl/6, created via a chemically induced point mutation in the gene encoding the enzyme phenylalanine hydroxylase (BTBRenu2 and C57enu2, respectively). Despite having the same levels of hyperphenylalaninemia (HPA), published results indicate differences in neural and behavioral phenotypes between the two backgrounds. To explore this difference further, the current study examines the genome-wide transcriptome of the prefrontal cortex (pFC), the brain region which is the most vulnerable to the negative effects of HPA. Regardless of the strain, the enu2 mutation upregulated the expression of several aminoacyl-tRNA synthetases and eukaryotic translation initiation factors, suggesting an essential modification in the protein translation process and supporting the downregulation of gene programs related to myelination. Accordingly, we deepened the exploration of cognitive dysfunctions in C57enu2− mice, showing a previously unreported working memory impairment under increasing information load. These findings identify convergent pFC molecular and cognitive alterations induced by HPA across distinct genetic backgrounds, providing clinically relevant insights into mechanisms that may contribute to executive dysfunctions in PKU.