Early in the course of prion disease, the connections between brain cells (synapses) are among the first structures to be damaged. This damage may be the first domino to fall in the cascade of toxicity, ultimately leading to the progressive degeneration of the brain observed later in the disease. This early ‘synaptotoxicity’ appears to be caused by prions interacting with a specific brain cell receptor, the NMDA receptor, resulting in hyperactivity and damage to synapses. How prions interact with the NMDA receptor to induce this hyperactivity remains unknown. We will use advanced electron microscopy and targeted labelling techniques to locate prions interacting with the NMDA receptor on the surface of brain cells and to capture images of this interaction. Using these images, we will build structural models that will not only reveal how prions interact with the receptor, but also inform strategies to prevent this toxic interaction.