NR AGBU
AU Johnston,A.R.; Fraser,J.R.; Jeffrey,M.J.; MacLeod,N.
TI Alterations in potassium currents may trigger neurodegeneration in murine scrapie
QU Experimental Neurology 1998 Jun; 151(2): 326-33
PT journal article
AB Conventional electrophysiological intracellular recording techniques were used to test the hypothesis that enhanced calcium entry via voltage-gated calcium channels or the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor-channel complex may be a primary pathological mechanism triggering neurodegeneration in scrapie and related diseases. This study was carried out at a time when cell loss is known to occur and when hippocampal pyramidal cells in area CA1 are rendered hyperexcitable following scrapie infection. There was no change to the NMDA receptor-mediated component of the Schaffer collateral evoked excitatory postsynaptic potential (EPSP) or the level of spontaneous firing activity of CA1 cells following addition of the specific NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV, 20 microM), to the perfusate in scrapie-infected mice, indicating that the NMDA receptor-channel complex is not compromised by scrapie. There was also no change seen in the non-NMDA mediated component of the EPSP. The calcium spike of CA1 pyramidal cells was not significantly altered by scrapie infection, indicating that high threshold voltage-gated Ca2+ channel function is not compromised by scrapie. By contrast, cells from scrapie-infected mice fired calcium spikes repetitively and the long, slow AHP, which in control cells inhibited repetitive firing, was absent. Cells from scrapie-infected mice showed more depolarized membrane potentials than controls but this difference in potential was no longer observed after exposure to TEA. These data indicate a loss of TEA-insensitive and TEA-sensitive potassium conductances. We suggest that altered potassium currents rather than increased calcium entry via voltage-sensitive calcium channels or the NMDA receptor complex may be the primary pathological mechanism triggering neurodegeneration in scrapie and related diseases.
MH 2-Amino-5-phosphonovalerate/pharmacology; Action Potentials/drug effects/physiology; Animal; Calcium/metabolism; Electrophysiology; Excitatory Amino Acid Antagonists/pharmacology; Excitatory Postsynaptic Potentials/drug effects/physiology; Hippocampus/*metabolism/physiopathology; Mice; Nerve Degeneration/*metabolism; Potassium/*metabolism; Potassium Channels/physiology; Pyramidal Cells/chemistry/physiology; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/physiology; Scrapie/*physiopathology; Support, Non-U.S. Gov't; Tetraethylammonium/pharmacology
AD Alex R. Johnston, Nikki MacLeod (nikki@ed.ac.uk), Department of Physiology, University Medical School, Teviot Place, Edinburgh, EH8 9AG, United Kingdom; Janet R. Fraser (janet.fraser@bbsrc.ac.uk), Institute for Animal Health, BBSRC and MRC, Neuropathogenesis Unit, Ogston Building, West Mains Road, Edinburgh EH9 3JF, Scotland, United Kingdom; Martin J. Jeffrey (m.jeffrey@vla.maff.gov.uk), VLA Lasswade Veterinary Laboratory, Pentlands Science Park, Bush Loan, Penicuik, Edinburgh EH26 OPZ, Scotland, United Kingdom
SP englisch
PO USA