mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo.

NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer's disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer's disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrP(C)-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.