Article

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

ABSTRACT

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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    • "Encouraging results have already been obtained using activin A as a neuroprotective agent in a rat lesion model of HD (Hughes et al., 1999). Recent work demonstrated that overexpression of mutant huntingtin induces phosphorylation of the NR2B subunit at tyrosine residue 1472 in vitro (Song et al., 2003), sensitizes NMDA receptors, and induces excitotoxicity in vivo (Zeron et al., 2002), indicating that cell loss in HD (and perhaps also in other neurodegenerative diseases; Li et al., 2011) may result from a shift in the balance of NMDA receptor signaling from the survival-promoting synaptic NMDA receptor toward extrasynaptic NMDA receptors that initiate cell death pathways (Hardingham et al., 2002; Hardingham and Bading, 2010; Parsons and Raymond, 2014). By showing that BDNF/ inhba signaling regulates and restores the balance in NMDA receptor signaling by affecting phosphorylation of the NR2B subunit at tyrosine residue 1472 and reducing the toxic, extrasynaptic NMDA-receptor-induced calcium influx, our data causally link these findings by delivering an explanation as to how activin A may rescue BDNF-deficient neurons from neuronal dysfunction and cell death associated with, or caused by, an imbalance in extrasynaptic versus synaptic NMDA receptor signaling. "
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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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