ene targeting is a useful approach to investigate the role of specific proteins which may be involved in sleep regulation and circadian rhythmicity. The prion protein (PrP) has been extensively investigated in the context of the prion diseases. These are inherited and transmissible disorders leading to neuronal degeneration in humans (e.g. Creuzfeldt Jackobs, Gerstmann-Straussler-Scheinker, Kuru and Fatal Familial Insomnia, FFI) and animals (scrapies and bovine encephalitis).
It is still a matter of debate whether the neuropathology in these diseases is elicited by the deposition of protease resistant protein (PrPRes), by the conversion of PrP to PrPRes, by the lack of the normal PrP function or by another mechanism. Mice devoid of PrP develop normally and show no abnormal phenotype, with the exception of mice with a deletion which encompassed a larger portion of the PrP gene, eliciting severe ataxia of the hind legs and loss of Purkinje cells at an advanced age. It has been proposed that PrP may play a role in synaptic function.
The typical features for FFI are progressive severe insomnia, loss of spindle activity in the EEG and disruption of the circadian rhythm of several hormones. The main neurological feature is hypometabolism, neuronal loss and astrogliosis in the thalamus. This indicates that PrP may be involved in regulating sleep and circadian rhythmicity. Our results in PrP knockout mice support this notion. Sleep was more fragmented, the increase of EEG slow waves within nonREM sleep episodes attained a lower level, and the response to sleep deprivation was stronger in PrP knockout mice compared to wild-type controls. The freerunning period of the activity rhythm in constant darkness was longer in the knockout mice compared to the controls, and was more stable in prolonged constant darkness compared to the progressive shortening of period over several weeks in the controls. The differences in sleep and circadian rhythms were restored towards the wild-type phenotype in transgenic mice PrP knockout mice which overexpressed the prion protein.
