Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons

Previous neurophysiological studies on prion protein deficient (Prnp(-/-)) mice have revealed a significant reduction of slow afterhyperpolarization currents (sI(AHP)) in hippocampal CA1 pyramidal cells. Here we aim to determine whether loss of PrPC. directly affects the potassium channels underlying sI(AHP) or if sI(AHP) is indirectly disturbed by altered intracellular Ca2+ fluxes. Patch-clamp measurements and confocal Ca2+ imaging in acute hippocampal slice preparations of Prnp(-/-) mice compared to littermate control mice revealed a reduced Ca2+ rise in CA1 neurons lacking PrPC following a depolarization protocol known to induce sI(AHP). Moreover, we observed a reduced Ca2+ influx via L-type voltage gated calcium channels (VGCCs). No differences were observed in the protein expression of the pore forming alpha 1 subunit of VGCCs Prnp(-/-) mice. Surprisingly, the beta 2 subunit, critically involved in the transport of the alpha 1 subunit to the plasma membrane, was found to be up-regulated in knock out hippocampal tissue. On mRNA level however, no differences could be detected for the alpha 1C, D and beta 2-4 subunits. In conclusion our data support the notion that lack of PrPC. does not directly affect the potassium channels underlying sI(AHP), but modulates these channels due to its effect on the intracellular free Ca2+ concentration via a reduced Ca2+ influx through L-type VGCCs.