Soluble amyloid-? oligomers (A?o) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular A?o bound to lipid-anchored PrPCactivates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple A?o-PrPCwith Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound A?o to activate Fyn. PrPCand mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. A?o-PrPCgenerates mGluR5-mediated increases of intracellular calcium inXenopusoocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by A?o-PrPC-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, A?o-PrPCcomplexes at the neuronal surface activate mGluR5 to disrupt neuronal function.