GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo
- 1 December 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (48), 20504-20509
- https://doi.org/10.1073/pnas.0908083106
Abstract
Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease.Keywords
This publication has 72 references indexed in Scilit:
- NMDA receptor subunits: function and pharmacologyCurrent Opinion in Pharmacology, 2007
- The role of NMDAR subtypes and charge transfer during hippocampal LTP inductionNeuropharmacology, 2007
- Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampusNeuropharmacology, 2007
- Glycogen synthase kinase‐3 inhibition is integral to long‐term potentiationEuropean Journal of Neuroscience, 2007
- Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivoHippocampus, 2006
- β-Amyloid-induced Dynamin 1 Degradation Is Mediated by N-Methyl-D-Aspartate Receptors in Hippocampal NeuronsJournal of Biological Chemistry, 2006
- Zinc Modulates Bidirectional Hippocampal Plasticity by Effects on NMDA ReceptorsJournal of Neuroscience, 2006
- Tumor Necrosis Factor-α Induces Neurotoxicity via Glutamate Release from Hemichannels of Activated Microglia in an Autocrine MannerPublished by Elsevier BV ,2006
- Soluble β-Amyloid1-40Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic SynapsesJournal of Neuroscience, 2005
- β‐amyloid inhibition of long‐term potentiation is mediated via tumor necrosis factorEuropean Journal of Neuroscience, 2005