Altered circadian function in a mouse model of phenylketonuria

Phenylketonuria (PKU) is a rare, metabolic disease caused by a mutation in the gene for the enzyme phenylalanine hydroxylase (PAH). The resulting enzyme defect reduces the transformation of phenylalanine (Phe) to tyrosine and causes the accumulation of Phe in blood and brain. This elevated Phe concentration obstructs the entry of essential amino acids, which serve as neurotransmitter precursors in the brain, affecting proper brain function. It has been observed that PKU is also associated with alterations in circadian rhythms and sleep patterns. However, available data are limited.
The Pah^enu2 mouse is a chemically induced mutant model that has high Phe levels similar to those of untreated, classic PKU patients. In the present study, we assessed circadian activity patterns of PKU mice by using passive infrared recording (PIR) sensors. Electroencephalogram (EEG) was used to examine their wakefulness and sleep cycles, along with their sleep homeostatic responses following 3 or 6 hours of sleep deprivation (SD).
The PIR data show altered diurnality and higher fragmentation in PKU mice. Notably, PKU mice exhibit previously undetected ‘spike wave’ EEG signals, detectable throughout wake and sleep stages. We are currently examining the EEG patterns in detail to fully the sleep patterns and the response to SD in PKU mice, compared to wild-type littermates.