In order to gain insights on the function of the cellular prion protein (PrP(C)) sleep and the levels of the stress hormones corticosterone (CORT) and the adrenocorticotropic hormone (ACTH) before and after sleep deprivation (SD) were compared in two wild type (WT) mice strains and the following three PrP(C) transgenic lines: mice null for PrP(C) (mPrP(0/0)) and mice with specific and central expression of PrP in neurons (NSE-HPrP/mPrP(0/0)) or in glia cells (GFAP-HPrP/mPrP(0/0)). After SD mPrP(0/0) mice showed a larger degree of sleep fragmentation and of latency to enter rapid eye movement (REM) and non-REM sleep (NREM) than WT. During sleep recovery, the amount of NREM sleep and the slow-wave activity (SWA) were reduced in mPrP(0/0) mice. After SD, CORT and ACTH levels have distinct patterns in WT and mPrP(0/0). The NREM and SWA deficit was restored in NSE-HPrP/mPrP(0/0) mice but not in GFAP-HPrP/mPrP(0/0). Hormonal profile was only partially restored in NSE-HPrP/mPrP(0/0) mice and was similar to that of mPrP(0/0) and GFAP-HPrP/mPrP(0/0) mice. These findings demonstrate that neuronal, but not non-neuronal, PrP(C) is involved in sleep homeostasis and sleep continuity. They also suggest that neuronal PrP(c)-dependent hormonal regulation of HPA axis may contribute to the sleep homeostasis.