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

Area of Science:

• Neuroscience
• Pathophysiology
• Prion Diseases

Background:

• Prion diseases exhibit diverse clinical presentations, indicating distinct underlying pathophysiological changes.
• Understanding variant Creutzfeldt-Jakob Disease (vCJD) pathophysiology is crucial for differentiating it from other prionopathies.

Purpose of the Study:

• To investigate the specific in vitro electrophysiological changes associated with vCJD.
• To elucidate the mechanisms underlying vCJD pathophysiology using a transgenic mouse model.

Main Methods:

• Transgenic mice expressing human prion protein were inoculated with human-derived vCJD prions.
• Electrophysiological studies, including paired-pulse stimulation of Schaffer collaterals, were conducted.
• Pharmacological experiments and computer simulations were employed to analyze NMDA receptor function.

Main Results:

• vCJD-inoculated mice exhibited hypersynchronous hippocampal bursting, absent in controls or mice with classical CJD prions.
• A significant increase in NMDA receptor-mediated excitation was observed in vCJD-inoculated mice.
• Increased NMDA receptor excitation was identified as necessary and sufficient for the observed bursting pattern.

Conclusions:

• The distinctive bursting pattern in vCJD is attributed to increased NMDA receptor-mediated excitation.
• These findings suggest a prion strain-specific gain-of-function mechanism in vCJD.
• The identified pathophysiological changes may account for the unique clinical manifestations of vCJD.