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

ABSTRACT: The mechanisms by which ?-amyloid (A?), a peptide fragment believed to contribute to Alzheimer's disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric A? requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. A? activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric A? 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 A? to produce synaptic depression and a switch in NMDAR composition. This A?-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer's disease.

SUBMITTER: Kessels HW

PROVIDER: S-EPMC3593880 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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

Kessels Helmut W HW Nabavi Sadegh S Malinow Roberto R

Proceedings of the National Academy of Sciences of the United States of America 20130219 10

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 i ...[more]

PMID: 23431156

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