Article

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

Center for Neural Circuits and Behavior, Departments of Neuroscience and Biology, University of California at San Diego, La Jolla, CA 92093.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2013; 110(10):4033-8. DOI: 10.1073/pnas.1219605110
Source: PubMed

ABSTRACT 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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