Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 106 (48): 20504-20509

Copyright © 2009 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / NEUROSCIENCE

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

Neng-Wei Hua,b, Igor Klyubina,b, Roger Anwylb,c, and Michael J. Rowana,b,1

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

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved October 14, 2009

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 Aβ1–42 -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNF{alpha} mediates this deleterious action of Aß was provided by the ability of TNF{alpha} antagonists to prevent Aβ1–42 inhibition of plasticity and the abrogation of a similar disruptive effect of TNF{alpha} using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNF{alpha}, Aβ1–42 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


Author contributions: N.-W.H., I.K., R.A., and M.J.R. designed research; N.-W.H. and I.K. performed research; and N.-W.H., I.K., R.A., and M.J.R. wrote the paper.

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease A{beta} in vivo.
I. Klyubin, T. Ondrejcak, J. Hayes, W. K. Cullen, A. J. Mably, D. M. Walsh, and M. J. Rowan (2013)
Phil Trans R Soc B 369, 20130147
   Abstract »    Full Text »    PDF »
Metabotropic NMDA receptor function is required for {beta}-amyloid-induced synaptic depression.
H. W. Kessels, S. Nabavi, and R. Malinow (2013)
PNAS 110, 4033-4038
   Abstract »    Full Text »    PDF »
Biochemistry of Amyloid {beta}-Protein and Amyloid Deposits in Alzheimer Disease.
C. L. Masters and D. J. Selkoe (2012)
Cold Spring Harb Perspect Med 2, a006262
   Abstract »    Full Text »    PDF »
Activation of NMDA Receptors Upregulates A Disintegrin and Metalloproteinase 10 via a Wnt/MAPK Signaling Pathway.
X.-Z. Wan, B. Li, Y.-C. Li, X.-L. Yang, W. Zhang, L. Zhong, and S.-J. Tang (2012)
J. Neurosci. 32, 3910-3916
   Abstract »    Full Text »    PDF »
Cellular prion protein is essential for oligomeric amyloid-{beta}-induced neuronal cell death.
W. Kudo, H.-P. Lee, W.-Q. Zou, X. Wang, G. Perry, X. Zhu, M. A. Smith, R. B. Petersen, and H.-g. Lee (2012)
Hum. Mol. Genet. 21, 1138-1144
   Abstract »    Full Text »    PDF »
Soluble A{beta} Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors.
S. Li, M. Jin, T. Koeglsperger, N. E. Shepardson, G. M. Shankar, and D. J. Selkoe (2011)
J. Neurosci. 31, 6627-6638
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882