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Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4033-8. doi: 10.1073/pnas.1219605110. Epub 2013 Feb 19.

Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression.

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Center for Neural Circuits and Behavior, Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093, USA.


The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer's disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer's disease.

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