Hippocampal bursts caused by changes in NMDA receptor-dependent excitation in a mouse model of variant CJD.
Prion diseases are heterogeneous in clinical presentation, suggesting that different prion diseases have distinct pathophysiological changes. To understand the pathophysiology specific to variant Creutzfeldt-Jakob Disease (vCJD), in vitro electrophysiological studies were performed in a mouse model in which human-derived vCJD prions were transmitted to transgenic mice expressing human instead of murine prion protein. Paired-pulse stimulation of the Schaffer collaterals evoked hypersynchronous bursting in the hippocampus of vCJD-inoculated mice; comparable bursts were never observed in control or Prnp knockout mice, or in mice inoculated with a strain of prion associated with classical CJD. Furthermore, NMDA receptor-mediated excitation was increased in vCJD-inoculated mice. Using pharmacological experiments and computer simulations, we demonstrate that the increase in NMDA receptor-mediated excitation is necessary and sufficient to explain the distinctive bursting pattern in vCJD. These pathophysiological changes appear to result from a prion strain-specific gain-of-function and may explain some of the distinguishing clinical features of vCJD.
Ratté
Stéphanie
S
Division of Neuroscience (Neurophysiology), Medical School, University of Birmingham, Edgbaston, Birmingham, UK. sratte@pitt.edu
Prescott
Steven A
SA
Collinge
John
J
Jefferys
John G R
JG
D000818:Animals; D003198:Computer Simulation; D007562:Creutzfeldt-Jakob Syndrome / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D055366:Synaptic Potentials / Q000235:genetics / Q000502:physiology*
C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D016194:Receptors, N-Methyl-D-Aspartate