Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices
Abstract
Soluble amyloid beta (Aβ) oligomers are widely accepted to be neurotoxic and lead to the memory loss and neuronal death observed in Alzheimer's disease (AD). Ample evidence suggests that impairment in glutamatergic signalling is associated with AD pathology. In particular, Aβ(1-42) is thought to affect N-methyl-d-aspartate (NMDA) receptor function and abolish the induction of long-term potentiation (LTP), which is regarded to be a phenomenon relevant to memory formation. The involvement of glutamatergic signalling in the pathology of AD is underscored by the therapeutic success of memantine, an uncompetitive NMDA receptor antagonist, used to treat patients with moderate to severe AD. In this study we show that Aβ(1-42) oligomers applied to acute murine hippocampal slices prevented, in a concentration-dependent manner, the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with a half maximal inhibitory concentration of around 2 nM (before oligomerization). The highest concentration of Aβ(1-42) oligomers (50 nM before oligomerization) completely blocked LTP (105 ± 1% potentiation versus 141 ± 3% in control) whereas scrambled Aβ(1-42) (50 nM) was without effect (144 ± 10% potentiation). Pre-incubation with memantine (1 μM) restored LTP in the presence of Aβ(1-42) (50 nM; 135 ± 5% potentiation). NMDA receptors containing the NR2B subunit have been proposed to play a particularly important role in excitotoxicity, functioning as extracellular "death receptors". The metabotropic glutamate receptor 5 (mGluR5) is mechanistically coupled to postsynaptic NMDA receptors. As such, allosteric sites on both receptors offer alternative means to modulate NMDA receptor function. We therefore tested low concentrations (each 300 nM) of allosteric antagonists of NR2B (Ro 25-6981, [R-(R∗,S∗)]-α-(4-Hydroxyphenyl)-β-methyl-4(phenylmethyl)-1-piperidine propanol hydrochloride) and mGluR5 receptors (MPEP, 2-methyl-6-(phenylethynyl)-pyridine). Both compounds restored LTP in the presence of Aβ(1-42) oligomers (50 nM, fEPSPs were potentiated to 129 ± 13% and 133 ± 7% respectively). Finally, we demonstrated that slices from mice heterozygous for NR2B receptor) in the forebrain are not susceptible to the toxic effects of Aβ(1-42) oligomers but express normal LTP (138 ± 6%). These experiments demonstrate that glutamate receptor antagonists delivered at concentrations which still allow physiological activities in vitro, are able to prevent Aβ(1-42) oligomer-induced synaptic toxicity and further support the glutamatergic system as a target for the development of improved symptomatic/neuroprotective treatments for AD.
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Protection is also afforded by antagonists of metabotropic mGluR5 receptors.
“protection also is afforded by antagonists of metabotropic mGluR5 receptors (Rammes et al., 2011; Renner et al., 2010; Wang et al., 2004).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Rammes et al., 2011
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- Authors
- Rammes, G., Hasenjäger, A., Sroka-Saidi, K., Deussing, J. M., & Parsons, C. G.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Merz (Germany) (DE)
- Corresponding author
- Parsons, Chris G.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 60
- Issue
- 6
- Pages
- 982-990
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2007495000
- Cited by
- 163
- References
- 56
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 6 · 2023: 2 · 2022: 15 · 2021: 9 · 2020: 7 · 2019: 9 · 2018: 13 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 15 · 2013: 10 · 2012: 11
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, amyloid-beta 42, NMDA receptor, NR2B subunit, metabotropic glutamate receptor 5, mGluR5, long-term potentiation, CA1, hippocampus, memantine, Ro 25-6981, allosteric antagonists, glutamatergic signalling, excitotoxicity, synaptotoxicity, Schaffer collaterals, tetanic stimulation, memory loss, neuroprotection, Alzheimer's disease therapeutics
- MeSH terms
- Animals, Electric Stimulation, Hippocampus, Male, Memantine, Mice, Inbred C57BL, Peptide Fragments, Phenols, Piperidines, Pyridines, Synapses, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Long-Term Potentiation, Receptors, Metabotropic Glutamate, Mice, Knockout, Excitatory Postsynaptic Potentials, Mice, Receptor, Metabotropic Glutamate 5, In Vitro Techniques
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