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 PrP(C.) directly affects the potassium channels underlying sI(AHP) or if sI(AHP) is indirectly disturbed by altered intracellular Ca(2+) fluxes. Patch-clamp measurements and confocal Ca(2+) imaging in acute hippocampal slice preparations of Prnp(-/-) mice compared to littermate control mice revealed a reduced Ca(2+) rise in CA1 neurons lacking PrP(C) following a depolarization protocol known to induce sI(AHP). Moreover, we observed a reduced Ca(2+) influx via l-type voltage gated calcium channels (VGCCs). No differences were observed in the protein expression of the pore forming alpha1 subunit of VGCCs Prnp(-/-) mice. Surprisingly, the beta2 subunit, critically involved in the transport of the alpha1 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 alpha1C, D and beta2-4 subunits. In conclusion our data support the notion that lack of PrP(C.) does not directly affect the potassium channels underlying sI(AHP), but modulates these channels due to its effect on the intracellular free Ca(2+) concentration via a reduced Ca(2+) influx through l-type VGCCs.
Fuhrmann
Martin
M
Center of Neuropathology and Prion Research, Ludwig Maximilians University, 81377 Munich, Germany.
Bittner
Tobias
T
Mitteregger
Gerda
G
Haider
Nicole
N
Moosmang
Sven
S
Kretzschmar
Hans
H
Herms
Jochen
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism*; D006706:Homeostasis; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000172:deficiency*; D017966:Pyramidal Cells / Q000378:metabolism* / Q000502:physiology
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D011498:Protein Precursors; D002118:Calcium