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

Neng-Wei Hu, Andrew J. Nicoll, Dainan Zhang, Alexandra J. Mably, Tiernan O’Malley, Silvia A. Purro, Cassandra Terry, John Collinge, Dominic M. Walsh and Michael J. Rowan ()
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Neng-Wei Hu: and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin
Andrew J. Nicoll: UCL Institute of Neurology, Queen Square
Dainan Zhang: and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin
Alexandra J. Mably: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Institute of Medicine
Tiernan O’Malley: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Institute of Medicine
Silvia A. Purro: UCL Institute of Neurology, Queen Square
Cassandra Terry: UCL Institute of Neurology, Queen Square
John Collinge: UCL Institute of Neurology, Queen Square
Dominic M. Walsh: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Institute of Medicine
Michael J. Rowan: and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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-PrPC-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

Date: 2014
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DOI: 10.1038/ncomms4374

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