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

• Published in: Nature communications 2014-03, Vol.5 (1), p.3374-3374, Article 3374
• Main Authors: Hu, Neng-Wei, Nicoll, Andrew J., Zhang, Dainan, Mably, Alexandra J., O’Malley, Tiernan, Purro, Silvia A., Terry, Cassandra, Collinge, John, Walsh, Dominic M., Rowan, Michael J.
• Format: Article
• Language: English
• Subjects: 13/1; 631/378/1689/1283; 631/378/2591/2593; 631/45/460; 9/26; 9/30; Amyloid beta-Peptides - metabolism; Animals; Hippocampus - metabolism; Humanities and Social Sciences; Long-Term Synaptic Depression - physiology; Male; multidisciplinary; Prions - metabolism; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5 - genetics; Receptor, Metabotropic Glutamate 5 - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4374

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. In Alzheimer's disease, the soluble amyloid beta peptide is known to modulate synaptic function by forming a complex with prion proteins and metabotropic glutamate receptors. Here, Hu et al. show that amyloid beta signalling via this complex facilitates the induction of long-term depression at synapses.