title: mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Neng-Wei
authors.initials: NW
authors.lastname: Hu
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nicoll
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Dainan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Mably
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Tiernan
authors.initials: T
authors.lastname: O'Malley
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Purro
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Terry
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Biotechnology Building, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006624:Hippocampus / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D011328:Prions / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D011328:Prions; D064529:Receptor, Metabotropic Glutamate 5