Neurobehavioral impairments of prion protein deficient mice in olfactory tasks: Towards a functional understanding of the cellular prion protein PrP(C)

The function of the cellular prion protein, PrPC , has remained mysterious since the making of the first PrP knockout mouse in 1992. This protein is both conserved and expressed widely, especially in brain. However the knockout mice are essentially normal, despite the report of multiple subtle phenotypes. Most studies of these mice have focused on hippocampal related functions such as spatial learning, but none has examined their olfactory behavior. Olfaction is a critical sensory modality for most animals, notably rodents. We observed PrPC expression in peripheral and central neurons of the olfactory system from embryonic times onward. In particular, we found that in both peripheral and central neurons, the postnatal localization of PrPC was axonal. Given this expression pattern, we examined whether PrP knockout mice exhibited behavioral deficits in olfactory tasks. In the so-called hidden cookie paradigm, PrP knockouts displayed hyposmic behavior both in their delayed retrieval of the cookie and their lesser improvement in a consecutive trial. The behavioral consequence of PrP deficiency was examined in a battery of genetically modified mice. Although the phenotype was masked by one genetic background, it was manifest in PrP knockouts on a total of three backgrounds. Furthermore, when PrPC was specifically reconstituted in neurons, the phenotype was rescued. PrP knockouts also display impaired behavior in a further task, the olfactory habituation assay. They however responded nor many to a strongly aversive olfactory stimulus, suggesting their deficit did not affect central pathways of innate aversive behavior. Based on electrophysiological recordings we concluded that PrP knockout mice had intact olfactory transduction in the olfactory epithelium and odor-evoked responses in the olfactory bulb (OB). Furthermore, olfactory receptor-specific axonal projections to the OB were preserved. Together, these results suggested the problem lay in higher centers. Using magnetic resonance imaging we discovered that metabolic activity, reflected by the cerebral blood volume of specific regions, was selectively affected in the PrP knockout. One such region was the entorhinal cortex, an integrative area that receives direct input from the olfactory bulb and relays information to the hippocampus. This region could potentially underlie the observed neurobehavioral deficits.