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Nat Commun. 2014 Mar 4;5:3374. doi: 10.1038/ncomms4374.

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

Author information

1
Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin, Dublin 2, Ireland.
2
Medical Research Council Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
3
Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

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-PrP(C)-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

PMID:
24594908
PMCID:
PMC4354159
DOI:
10.1038/ncomms4374
[Indexed for MEDLINE]
Free PMC Article

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