A phenylketonuria mouse model exhibits EEG spike-wave discharges: Effects of sleep deprivation and low-Phe diet

Phenylketonuria (PKU) is an inherited metabolic disorder characterized by phenylalanine hydroxylase deficiency and elevated phenylalanine (Phe) levels in blood and brain, causing neurotoxicity and brain dysfunction. Elevated Phe levels may alter brain activity, as poor dietary control is linked to abnormal EEGs. However, knowledge on these electrophysiological characteristics remains limited. The current study applied electroencephalogram (EEG) recordings of brain activity in PAH^enu2 mice, which have elevated Phe levels resembling untreated PKU patients. EEG recordings revealed frequent spontaneous spike wave discharges (referred to as SWDs) that predominantly occurred during wakefulness and rapid-eye-movement (REM) sleep and were accompanied by reduced muscle tone. Furthermore, SWD incidence was exacerbated by sleep deprivation and normalized during recovery sleep. While the overall amount of sleep was unchanged, PKU mice exhibited more fragmented sleep and mildly altered EEG slow-wave activity rebound following sleep deprivation. Notably, decreasing blood Phe levels through dietary treatment reduced SWD activity under baseline conditions, though it only partly prevented the elevated SWD expression during sleep deprivation. In conclusion, this study in the PAH^enu2 mouse model demonstrates that extremely high Phe levels can lead to abnormal brain activity including the development of SWDs. Moreover, the findings suggest that SWD expression can be reduced through dietary restriction of Phe.