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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Neng-Wei Hu & Andrew J. Nicoll & Dainan Zhang & Alexandra J. Mably & Tiernan O’Malley & Silvia A. Purro & Cassandra Terry & John Collinge & Dominic M. Walsh & Michael J. Rowan, 2014. "mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4374
    DOI: 10.1038/ncomms4374
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