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Hippocampal bursts caused by changes in NMDA receptor-dependent excitation in a mouse model of variant CJD.

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.
AuthorsStéphanie Ratté, Steven A Prescott, John Collinge, John G R Jefferys
JournalNeurobiology of disease (Neurobiol Dis) Vol. 32 Issue 1 Pg. 96-104 (Oct 2008) ISSN: 1095-953X [Electronic] United States
PMID18638557 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • PRNP protein, human
  • Prion Proteins
  • Prions
  • Receptors, N-Methyl-D-Aspartate
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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