Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration

GR Mallucci, Stephanie Ratte, E Asante, J Linehan, I Gowland, John Jefferys, J Collinge

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    310 Citations (Scopus)


    Prion protein (PrP) plays a crucial role in prion disease, but its physiological function remains unclear. Mice with gene deletions restricted to the coding region of PrP have only minor phenotypic deficits, but are resistant to prion disease. We generated double transgenic mice using the Cre-loxP system to examine the effects of PrP depletion on neuronal survival and function in adult brain. Cre-mediated ablation of PrP in neurons occurred after 9 weeks. We found that the mice remained healthy without evidence of neurodegeneration or other histopathological changes for up to 15 months post-knockout. However, on neurophysiological evaluation, they showed significant reduction of afterhyperpolarization potentials (AHPs) in hippocampal CA1 cells, suggesting a direct role for PrP in the modulation of neuronal excitability. These data provide new insights into PrP function. Furthermore, they show that acute depletion of PrP does not affect neuronal survival in this model, ruling out loss of PrP function as a pathogenic mechanism in prion disease and validating therapeutic approaches targeting PrP.
    Original languageEnglish
    Pages (from-to)202-210
    Number of pages9
    JournalThe EMBO journal
    Issue number3
    Publication statusPublished - 1 Feb 2002


    • prion protein
    • prion disease
    • Cre-loxP system
    • afterhyperpolarization potential


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