ALTERATIONS IN POTASSIUM CURRENTS MAY TRIGGER NEURODEGENERATION IN MURINE SCRAPIE

Conventional electrophysiological intracellular recording techniques w ere used to test the hypothesis that enhanced calcium entry via voltag e-gated calcium channels or the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor-channel complex may be a primary pathological mech anism triggering neurodegeneration in scrapie and related diseases. Th is study was carried out at a time when cell loss is known to occur an d when hippocampal pyramidal cells in area CA1 are rendered hyperexcit able following scrapie infection. There was no change to the NMDA rece ptor-mediated component of the Schaffer collateral evoked excitatory p ostsynaptic potential (EPSP) or the level of spontaneous firing activi ty of CA1 cells following addition of the specific NMDA receptor antag onist, 2-amino-5-phosphonovaleric acid (APV, 20 mu M), to the perfusat e in scrapie-infected mice, indicating that the NMDA receptor-channel complex is not compromised by scrapie. There was also no change seen i n the non-NMDA mediated component of the EPSP. The calcium spike of CA 1 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 m ice fired calcium spikes repetitively and the long, slow AHP, which in control cells inhibited repetitive firing, was absent. Cells from scr apie-infected mice showed more depolarized membrane potentials than co ntrols but this difference in potential was no longer observed after e xposure to TEA. These data indicate a loss of TEA-insensitive and TEA- sensitive potassium conductances. We suggest that altered potassium cu rrents rather than increased calcium entry via voltage-sensitive calci um channels or the NMDA receptor complex may be the primary pathologic al mechanism triggering neurodegeneration in scrapie and related disea ses. (C) 1998 Academic Press.