Metabotropic NMDA receptor function is required for -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: 9.67). 03/2013; 110(10):4033-8. DOI: 10.1073/pnas.1219605110
Source: PubMed


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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    • "Interestingly, subsequent research into the properties of Ab has revealed that excessive levels of Ab inhibit activity-dependent synaptic plasticity, the basis for learning and memory (Koffie et al., 2011; LaFerla et al., 2007). For example, infusion of Ab in rats transiently impairs cognitive function (Cleary et al., 2005), and acute neuronal overproduction of Ab blocks synaptic plasticity (Kessels et al., 2013; Wei et al., 2010). These unique synaptotoxic properties, together with its accumulation in both familial and sporadic AD, established Ab as a key player in AD. "
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    • "In the present study we demonstrate changes in Src-dependent signaling pathways involving modified GluN2B subunit and Dab1 phosphorylation, and actin cytoskeleton polymerization in post-synaptic sites in the 3xTg-AD mice model of AD. Direct activation of NMDARs by Aβ was previously described in AD (Texido et al., 2011; Costa et al., 2012; Kessels et al., 2013). We previously demonstrated that Aβ 1–42 immediately disturbs intracellular Ca 2+ homeostasis (Ferreira et al., 2012), namely through ER stress (Costa et al., 2012), and causes microtubule deregulation (Mota et al., 2012) by interacting with GluN2B-containing NMDARs, as observed in cortical and hippocampal neurons, revealing an important role of this NMDAR subunit. "
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