GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo

Neng-Wei Hu^a,b, Igor Klyubin^a,b, Roger Anwyl^b,c, and Michael J. Rowan^a,b,1

^aDepartment of Pharmacology and Therapeutics, ^bTrinity College Institute of Neuroscience, and ^cDepartment of Physiology, Trinity College Dublin, Dublin 2, Ireland

Received for publication July 19, 2009.

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-β protein (Aβ) 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 Aβ 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 Aβ_1–42 -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNF mediates this deleterious action of Aß was provided by the ability of TNF antagonists to prevent Aβ_1–42 inhibition of plasticity and the abrogation of a similar disruptive effect of TNF using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNF, Aβ_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.

Key Words: Alzheimer's disease • amyloid-β protein oligomers • glutamate

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0908083106/DCSupplemental.

¹To whom correspondence should be addressed. E-mail: mrowan{at}tcd.ie

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