Abstract |
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.
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Authors | Stéphanie Ratté, Steven A Prescott, John Collinge, John G R Jefferys |
Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 32
Issue 1
Pg. 96-104
(Oct 2008)
ISSN: 1095-953X [Electronic] United States |
PMID | 18638557
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- PRNP protein, human
- Prion Proteins
- Prions
- Receptors, N-Methyl-D-Aspartate
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Topics |
- Animals
- Computer Simulation
- Creutzfeldt-Jakob Syndrome
(pathology, physiopathology)
- Disease Models, Animal
- Hippocampus
(metabolism, pathology, physiology)
- Humans
- Mice
- Mice, Knockout
- Mice, Transgenic
- Prion Proteins
- Prions
(genetics, physiology)
- Receptors, N-Methyl-D-Aspartate
(physiology)
- Synaptic Potentials
(genetics, physiology)
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