title: Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression.
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.
authors: Center for Neural Circuits and Behavior, Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Helmut W
authors: HW
authors: Kessels
authors: Sadegh
authors: S
authors: Nabavi
authors: Roberto
authors: R
authors: Malinow
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016291:Dizocilpine Maleate; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C121001:NR2B NMDA receptor