Soluble A Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2011; 31(18):6627-38. DOI: 10.1523/JNEUROSCI.0203-11.2011
Source: PubMed


In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells, AD cortex, or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors ifenprodil and Ro 25-6981. Soluble Aβ enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor dl-threo-β-benzyloxyaspartic acid. Downstream, an Aβ-mediated rise in p38 mitogen-activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.

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    • "When LTP was induced by 1–3 bouts of TBS under physiological recording conditions, there was no difference between wt and PS2APP mice (Fig. 1B). Since many previous studies have shown that GluN2B-NMDAR antagonists rescue impairment of LTP caused by acute application of Aβ (Li et al., 2011; Olsen and Sheng, 2012; Rammes et al., 2011; Ronicke et al., 2011), we determined whether the LTP in PS2APP mice could be altered by the selective GluN2B antagonist Ro25. To our surprise, while Ro25 did not affect wt LTP, a significant reduction in LTP was seen in slices from PS2APP mice in the presence of Ro25 (Fig. 1C, D, F). "
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    ABSTRACT: GluN2B subunit containing NMDARs (GluN2B-NMDARs) mediate pathophysiological effects of acutely applied Amyloid Beta (Aβ), including impaired long-term potentiation (LTP). However, in transgenic Alzheimer's disease (AD) mouse models which feature gradual Aβ accumulation, the function of GluN2B-NMDARs and their contribution to synaptic plasticity are unknown. Therefore, we examined the role of GluN2B-NMDARs in synaptic function and plasticity in the hippocampus of PS2APP transgenic mice. Although LTP induced by theta burst stimulation (TBS) was normal in PS2APP mice, it was significantly reduced by the selective GluN2B-NMDAR antagonist Ro25-6981 (Ro25) in PS2APP mice, but not wild type (wt) mice. While NMDARs activated by single synaptic stimuli were not blocked by Ro25, NMDARs recruited during burst stimulation showed larger blockade by Ro25 in PS2APP mice. Thus, the unusual dependence of LTP on GluN2B-NMDARs in PS2APP mice suggests that non-synaptic GluN2B-NMDARs are activated by glutamate that spills out of synaptic cleft during the burst stimulation used to induce LTP. While long-term depression (LTD) was normal in PS2APP mice, and Ro25 had no impact on LTD in wt mice, Ro25 impaired LTD in PS2APP mice, again demonstrating aberrant GluN2B-NMDAR function during plasticity. Together these results demonstrate altered GluN2B-NMDAR function in a model of early AD pathology that has implications for the therapeutic targeting of NMDARs in AD. Copyright © 2014. Published by Elsevier Inc.
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    • "Several studies have reported that Aβ oligomers negatively modulate synaptic plasticity (Walsh et al., 2002; Cleary et al., 2005; Li et al., 2011; Ferreira and Klein, 2011). Previously, we showed that Aβ oligomers also reduce synaptic efficacy and impair hippocampal synaptic transmission, mainly by decreasing the NMDA and AMPA receptor currents , which is potentially caused by a reduction in the levels of PSD-95 and the number of synaptic contacts (Cerpa et al., 2010). "
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    • "Indeed, the NR2B inhibitor Ro25-6981 could attenuate the death of neuronal cells in Ab 25e35 -WT mice. The activation of extrasynaptic NMDAr has been reported to trigger the cAMP response element-binding protein (CREB) shut-off pathway leading to cell death (Li et al., 2011). Tackenberg et al. (2013) have reported that the inhibition of NR2B abolishes Ab-induced toxicity by preventing the activation of glycogen synthesis kinase-3b. "
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