Glun2b Subunit-Containing NMDA Receptor Antagonists Prevent Aβ
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Corrections PHYSICS MICROBIOLOGY Correction for “Distortions and stabilization of simple-cubic Correction for “Chemical sensing in mammalian host-bacterial calcium at high pressure and low temperature,” by Wendy L. Mao, commensal associations,” by David T. Hughes, Darya A. Terek- Lin Wang, Yang Ding, Wenge Yang, Wenjun Liu, Duck Young hova, Linda Liou, Carolyn J. Hovde, Jason W. Sahl, Arati V. Kim, Wei Luo, Rajeev Ahuja, Yue Meng, Stas Sinogeikin, Jinfu Patankar, Juan E. Gonzalez, Thomas S. Edrington, David A. Shu, and Ho-kwang Mao, which appeared in issue 22, June 1, Rasko, and Vanessa Sperandio, which appeared in issue 21, May 25, 2010, of Proc Natl Acad Sci USA (107:9831–9836; first published 2010, of Proc Natl Acad Sci USA (107:9965–9968; first published May 10, 2010; 10.1073/pnas.1002551107). May 17, 2010; 10.1073/pnas.1005279107). ’ fi The authors note that the following statement should be The authors note that due to a printer s error, the af liation added to the Acknowledgments: “V.S. was supported by Na- information for Wendy L. Mao was incorrect. The correct in- tional Institutes of Health Grant AI077613.” stitution name is SLAC. The authors would also like to note that Fig. 5 was incorrect as www.pnas.org/cgi/doi/10.1073/pnas.1008458107 shown. The corrected figure and its legend appear below. NEUROSCIENCE Correction for “GluN2B subunit-containing NMDA receptor an- Phonon DOS (states/meV atom) tagonists prevent Aβ-mediated synaptic plasticity disruption in 50 vivo,” by Neng-Wei Hu, Igor Klyubin, Roger Anwy, and Michael J. 40 Rowan, which appeared in issue 48, December 1, 2009, of Proc Natl Acad Sci USA (106:20504–20509; first published November 16, 30 2009; 10.1073/pnas.0908083106). 20 The authors note that the author name Roger Anwy should have appeared as Roger Anwyl. The corrected author line appears 10 below. The online version has been corrected. Frequency (meV) Frequency a,b a,b b,c 0 Neng-Wei Hu ,IgorKlyubin , Roger Anwyl ,andMichaelJ. a,b,1 Y S R T 0.1 0.2 Rowan Fig. 5. Phonon dispersion relation (Left) and density of states (DOS) (Right) www.pnas.org/cgi/doi/10.1073/pnas.1007564107 for pm Ca-VI. www.pnas.org/cgi/doi/10.1073/pnas.1007813107 12734 | PNAS | July 13, 2010 | vol. 107 | no. 28 www.pnas.org Downloaded by guest on September 27, 2021 GluN2B subunit-containing NMDA receptor antagonists prevent A-mediated synaptic plasticity disruption in vivo Neng-Wei Hua,b, Igor Klyubina,b, Roger Anwyl b,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 review July 19, 2009) Currently, treatment with the relatively low-affinity NMDA recep- NMDARs, A-induced effects can be selectively mediated tor antagonist memantine provides limited benefit in Alzheimer’s through GluN2A over GluN2B subunits (18) and memantine can disease (AD). One probable dose-limiting factor in the use of preferentially block GluN2C/D- over GluN2A/B-containing memantine is the inhibition of NMDA receptor-dependent synaptic NMDARs (19, 20), but see ref. 21. plasticity mechanisms believed to underlie certain forms of mem- In the light of these findings we postulated that protection ory. Moreover, amyloid- protein (A) oligomers that are impli- against A inhibition of NMDAR-dependent LTP might be cated in causing the cognitive deficits of AD potently inhibit this achieved with doses of GluN2 subtype selective agents below the form of plasticity. Here we examined if subtype-preferring NMDA threshold for impairing such plasticity on their own. Further- receptor antagonists could preferentially protect against the inhi- more, since deleterious effects of Aß in vitro are dependent on bition of NMDA receptor-dependent plasticity of excitatory syn- TNF␣ action (22) and NMDAR-TNF␣ synergism (23) we also aptic transmission by A in the hippocampus in vivo. Using doses investigated TNF␣’s role in the synaptic plasticity impairing that did not affect control plasticity, antagonists selective for effects of Aß in vivo. NMDA receptors containing GluN2B but not other GluN2 subunits prevented A1–42 -mediated inhibition of plasticity. Evidence that Results ␣ the proinflammatory cytokine TNF mediates this deleterious Abrogation of A-Mediated Disruption of Hippocampal Synaptic ␣ action of Aß was provided by the ability of TNF antagonists to Plasticity in Vivo by Antagonists Selective for GluN2B-Containing  prevent A 1–42 inhibition of plasticity and the abrogation of a NMDARs. The role of different NMDAR subtypes in mediating ␣ similar disruptive effect of TNF using a GluN2B-selective antag- the inhibitory effect of A on high frequency stimulation (HFS) onist. Moreover, at nearby synapses that were resistant to the induction of LTP at hippocampal CA1 synapses was assessed in ␣  inhibitory effect of TNF ,A 1–42 did not significantly affect plas- vivo, using antagonists for different GluN2 subunits. We com- ticity. These findings suggest that preferentially targeting GluN2B pared the effect of the antagonist NVP-AAM077 with approx- subunit-containing NMDARs may provide an effective means of imately 10-fold selectivity for GluN2A over GluN2B and ap- preventing cognitive deficits in early Alzheimer’s disease. proximately 2-fold over GluN2C/D, the antagonist ifenprodil which has Ͼ approximately 200-fold selectivity for GluN2B over ͉  ͉ Alzheimer’s disease amyloid- protein oligomers glutamate other GluN2 subunits, and the antagonist UBP141 with Ͼ approximately 5-fold selectivity for GluN2C/D over GluN2A/B lutamatergic processes are strongly implicated in causing (7, 24). First we titrated the agents against LTP to find doses that Gand mediating the symptoms of Alzheimer’s disease (AD) were approximately half the threshold for inhibition of (1). Early studies found that AD-associated amyloid -protein NMDAR-dependent synaptic plasticity (Fig. S1). Intracerebro- (A) promoted glutamatergic excitotoxicity. More recently A ventricular injection of NVP-AAM077 (125 pmol, 129.5 Ϯ 4.3% was discovered to form soluble oligomers that rapidly and pre-HFS mean baseline EPSP amplitude Ϯ SEM, at 3 h post- potently disrupt glutamatergic synapses and plasticity mecha- HFS, n ϭ 5), ifenprodil (3 nmol, 133.9 Ϯ 5.3%, n ϭ 5) or UBP141 nisms underlying cognitive function, including long-term poten- (6.25 nmol, 133.8 Ϯ 6.5%, n ϭ 4) had no significant effect alone tiation (LTP), in the absence of cell death, providing an expla- on LTP induction (P Ͼ 0.05 compared with vehicle-injected nation for the cognitive deficits in AD (2–4). controls; P Ͻ 0.05 compared with baseline; two-way ANOVA Apart from anticholinesterases, memantine, a low-affinity with repeated measures and paired Student’s t tests) (Fig. 1). NMDA receptor (NMDAR) antagonist (5), is the only currently Importantly, using these relatively low doses, of the three approved treatment for clinical dementia of the Alzheimer type.  compounds tested only the GluN2B-selective agent ifenprodil Although memantine can partially protect against A -mediated prevented the inhibition of LTP by soluble A . In animals disruption of LTP at synapses that requires NMDAR activation 1–42 that were coinjected with ifenprodil and A1–42 (80 pmol, i.c.v.), for its induction, it also inhibits LTP over an overlapping dose the conditioning HFS induced LTP (125.7 Ϯ 6.5%, n ϭ 6, P Ͻ range, presumably because of a relatively poor discrimination 0.05 compared with baseline; P Ͻ 0.05 compared with A between antagonism of physiological and disruptive NMDAR 1–42 alone, 102.1 Ϯ 2.2%, n ϭ 6) that was similar in magnitude to activation (6). Newer subtype selective NMDAR antagonists (7) vehicle-injected controls (133.1 Ϯ 5.5%, n ϭ 6; P Ͼ 0.05). In potentially could increase the dose range over which a beneficial contrast, coinjection of A with the GluN2A-selective NVP- effect is obtained if the LTP-disrupting actions of A and of 1–42 NMDAR antagonists are preferentially mediated by different NMDARs. Indeed the GluN2B (formerly known as NR2B or Author contributions: N.-W.H., I.K., R.A., and M.J.R. designed research; N.-W.H. and I.K. NMDA-R2B) (8) subunit has been implicated in regulating the performed research; and N.-W.H., I.K., R.A., and M.J.R. wrote the paper. actions and localization of A oligomers, and A oligomers have The authors declare no conflict of interest. been reported to promote endocytosis of GluN2B-containing This article is a PNAS Direct Submission. receptors (9–13), whereas both synaptic GluN2A- and GluN2B- 1To whom correspondence should be addressed. E-mail: [email protected]. containing NMDARs play key roles in LTP induction (14–17). This article contains supporting information online at www.pnas.org/cgi/content/full/ On the other hand, in cultured cells expressing cloned 0908083106/DCSupplemental. 20504–20509 ͉ PNAS ͉ December 1, 2009 ͉ vol. 106 ͉ no. 48 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0908083106 Fig. 2. Dose-dependence of the effects of subtype-selective NMDAR antag- onists on the inhbition of LTP by A1–42.(A) Neither pretreatment with the GluN2A antagonist NVP-AAM077 (125 pmol, n ϭ 5; and 250 pmol, n ϭ 4, i.c.v.) nor the GluN2C/D antagonist UBP141 (6.25, n ϭ 4; and 12.5 pmol, n ϭ 4, i.c.v.) significantly affected the inhibition of LTP by A1–42 (80 pmol, i.c.v., n ϭ 6 for A1–42 alone) (P Ͼ 0.05, one-way ANOVA). (B) In contrast, pretreatment with the GluN2B antagonist Ro 25–6981 (3 mg/kg, n ϭ 4; 6 mg/kg, n ϭ 6; and 12 mg/kg, n ϭ 4, i.p.) significantly (P Ͻ 0.05) reduced the A1–42-mediated inhibition of LTP (n ϭ 7 for A1–42 alone).