MGlu5 Receptors and Cellular Prion Protein Mediate Amyloid-β-facilitated Synaptic Long-term Depression in Vivo

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Mar 6

PMID 24594908

Citations 100

Authors

Neng-Wei Hu

Andrew J Nicoll

Dainan Zhang

Alexandra J Mably

Tiernan OMalley

Silvia A Purro

Cassandra Terry

John Collinge

Dominic M Walsh

Michael J Rowan

Affiliations

Soon will be listed here.

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.

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