STUDIO DEL RUOLO DELLA PROTEINA PRIONICA NELLA REGOLAZIONE DEL SONNO MEDIANTE L'UTILIZZO DI MODELLI MURINI TRANSGENICI

Introduction: an inherited form of Creutzfeldt-Jakob disease (CJD) is linked to the D178N/V129 mutation in the prion protein (PrP) gene. CJD is usually characterized by motor disorders, cognitive impairment and electroencephalographic alterations but recently sleep modification have been described. Moreover a role for PrP in sleep has been proposed on the basis of data collected in Knock-out mice. We generated a new mouse model of CJD (Tg(CJD)) that express the murine homologue of the D178N/V129 human mutation. We used as control mice Knock-out (KO) for the PrP, mice that over-express the normal form of the PrP Tg(WT) and Wt mice. Goals: 1) the characterization of Tg(CJD) mice 2) the study of the evolution during aging of sleep and EEG patterns in our CJD model and in KO and Tg(WT) mice 3) the study of response to sleep deprivation in all our strains. Materials: mice were anesthetized and instrumented for chronic EEG recordings, using standard techniques. Body movements were detected by means of an infrared sensor. Mice were individually housed in soundproof rooms, and maintained on a 12 hours light:dark cycle, at an ambient temperature between 23 and 24 °C. The study of the evolution of sleep patterns over time was conducted using animals of 3 different ages for each strain (6, 12 and 18 months). Sleep deprivation was carried out by means of gentle handling and lasted 6 hours starting from the beginning of light phase. Results: 18 months old Tg(CJD) mice showed a striking reduction in the amount of REM sleep compared to control strains. They also showed abundance of EEG alterations that remind those described in humans and motor alterations typical of CJD. The decrease in REM sleep is already present at 12 months of age in Tg(CJD) mice. Tg(CJD) and KO mice showed a flattening of the circadianity of sleep/wake cycle at 12 and 18 months of age. Sleep deprivation analysis showed a loss of rebound of REM sleep in mice with alterations of PrP. Conclusions: We propose that Tg(CJD) mice establish the first transgenic animal model of a genetic prion disease recapitulating cognitive, motor and neurophysiological abnormalities of the human disorder. We also propose that REM sleep decrease in Tg(CJD) mice is an early sign of CJD and could be a new tool for rapid diagnosis of this disease.