title: Alterations in potassium currents may trigger neurodegeneration in murine scrapie.
abstract: 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 Schäffer 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.
authors.affiliation: Department of Physiology, University Medical School, Teviot Place, Edinburgh, EH8 9AG, United Kingdom.
authors.forename: A R
authors.initials: AR
authors.lastname: Johnston
authors.forename: J R
authors.initials: JR
authors.lastname: Fraser
authors.forename: M
authors.initials: M
authors.lastname: Jeffrey
authors.forename: N
authors.initials: N
authors.lastname: MacLeod
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology; D017966:Pyramidal Cells / Q000737:chemistry / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D012608:Scrapie / Q000503:physiopathology*; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D015221:Potassium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D019789:Tetraethylammonium; D015763:2-Amino-5-phosphonovalerate; D011188:Potassium; D002118:Calcium