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.synapse | ion-flow independent | amyloid-beta | NR2A | NR2B

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

“…We ascertained that the majority of tdTomato-expressing neurons produced APP CT100 without affecting their membrane resistance (Fig. S1), supporting previous demonstrations that in these conditions the health of the neurons is not affected by Sindbis infection (7,11,19). WT neurons that expressed APP CT100 showed decreased AMPAR currents (P < 0.01) (Fig.…”

“…2B). As previously shown (11), APP CT100 expression in WT neurons selectively affected NMDAR currents mediated by GluN2B (P = 0.01) (Fig. 2 B and E) but not those mediated by GluN2A (P = 0.4) (Fig.…”

“…1A) and reduced AMPA/NMDA ratios (P = 0.03) (Fig. 1C), which have been shown to be caused by increased neuronal production of Aβ (7,11). In CA1 neurons of GluA3-deficient organotypic slices the AMPA/NMDA ratios were reduced 35% on average compared with WT CA1 neurons (P = 0.05) (Fig.…”

“…Neurons that overexpress APP or are exposed to Aβ oligomers show synaptic depression, a loss of dendritic spines, and a reduced capacity for synaptic plasticity (7)(8)(9)(10). For all these effects to occur, NMDA receptor (NMDAR) activity is required (7,(11)(12)(13). Aβ oligomers trigger an NMDAR-dependent signaling pathway that leads to synaptic depression through the removal of AMPA receptors (AMPARs) and NMDARs from synapses (7,11,14).…”

“…For all these effects to occur, NMDA receptor (NMDAR) activity is required (7,(11)(12)(13). Aβ oligomers trigger an NMDAR-dependent signaling pathway that leads to synaptic depression through the removal of AMPA receptors (AMPARs) and NMDARs from synapses (7,11,14). Interestingly, a blockade of AMPAR endocytosis prevents the depletion of NMDARs and a loss of spines (15,16), suggesting that the removal of AMPARs from synapses is critical for this pathway to induce synaptic failure.…”