Prion protein affects Ca2+-activated K+ currents in cerebellar Purkinje cells

The prion protein (PrPC) has a primary role in the pathogenesis of transmis sible spongiform encephalopathies. Its physiological function is not known yet. Altered late afterhyperpolarization has been observed in hippocampal C A1 pyramidal cells of prion protein-deficient mice (Prnp(0/0) mice) presuma bly caused by a disruption of Ca2+-activated K+ currents. An alteration of these currents has been recently described in scrapie-infected animals, and loss of function of PrPC has been put forward as one possible pathophysiol ogical mechanism in prion diseases. This work focuses on patch-clamp studie s of Ca2+-activated K+ currents in cerebellar Purkinje cells in the slice p reparation of Prnp(0/0) mice as well as of transgenic mice. A significant c orrelation between PrPC expression in Purkinje cells and the maximal amplit ude of TEA-insensitive Ca2+-activated K+ currents was observed, with reduce d current amplitudes in Prnp(0/0) mice and a rescue of the phenotype in tra nsgenic mice where PrPC had been reintroduced. Further studies of the intra cellular free calcium concentration revealed an alteration of the maximal i ncrease of intracellular calcium concentration with depolarization in the P rnp(0/0) mouse Purkinje cells. These data provide strong evidence that Ca2-activated K+ currents in Prnp(0/0) mice are reduced due to an alteration o f intracellular calcium homeostasis. (C) 2001 Academic Press.