Insights in the Regional Distribution and Physiological Role of the Cellular Prion Protein in the Central Nervous System of Mammalian Organisms

The cellular form of the prion protein (PrPC) is a sialoglycoprotein ubiquitously expressed in the central nervous system (CNS) of mammalian species along the neurodevelopment and in the adulthood. The PrPC localization in the brain has attracted interest because of its involvement in fatal neurodegenerative disorders, denoted as transmissible spongiform encephalopathies. In mammals, PrPC is expressed early in embryogenesis, and in the adulthood it reaches its highest levels in the neurons of the encephalon and spinal cord. The protein is also found at lower levels in glial cells of the CNS, as well as in almost all peripheral cell types. By combining in situ hybridization and immunohistochemical techniques, we show the earliest expression of the protein in mouse hippocampus, thalamus and hypothalamus. In particular, specific white matter fiber tracts in mouse CNS (the hippocampal fimbria, the stria terminalis, and the fasciculus retroflexus) show the highest expression of the protein. To extend our understanding of varying PrPC expression profiles in different mammals, we carried out a detailed expression analysis of PrPC distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). No naturally occurring prion diseases have been reported yet for this species. Compared with mice, in opossums we detected lower levels of PrPC in the white matter fiber bundles of the CNS. This result might offer new insights into a possible involvement of PrPC in the varying susceptibility to prion diseases for different mammals. The different distribution of PrPC in the hippocampal layers of mammals led us to hypothesize a different physiological relevance of PrPC in this region. To better understand this issue, we used PrP knock-out mice, in which PrPC is not expressed in the hippocampal strata. We observed that the absence of PrPC impairs the signaling pathway promoted by Reelin, a protein of the extracellular matrix expressed in the stratum lacunosum molecolare and hippocampus of the early postnatal mouse. Overall, our findings suggest a possible role for PrPC in the modulation of the events triggered by the Reelin-signaling pathway in the developmental mouse hippocampus.