Hippocampal bursts caused by changes in NMDA receptor-dependent excitation in a mouse model of variant CJD
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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.
|Number of pages||9|
|Journal||Neurobiology of Disease|
|Publication status||Published - 1 Oct 2008|
- attractor network, variant CJD, prion, computer simulations, electrophysiology, hippocampus, burst, transmissible spongiform encephalopathy, NMDA