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Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Open accessAbstract
There is a long-standing paradox that NMDA (N-methyl-D-aspartate) receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation of synaptic NMDARs, acting primarily through nuclear Ca(2+) signalling, leads to the build-up of a neuroprotective 'shield', whereas stimulation of extrasynaptic NMDARs promotes cell death. These differences result from the activation of distinct genomic programmes and from opposing actions on intracellular signalling pathways. Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling.
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“research suggests that synaptic NMDAR transmission promotes cell survival and that extra-synaptic NMDARs promote cell death through p38MAPK inhibition and activation, respectively [25].”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Augmented release of glutamate from astrocytes has been shown to be decrease brain-derived neurotrophic factor and increase excitotoxicity (Hardingham and Bading, 2010).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Hardingham and Bading, 2010
Experimental — accuracy not yet measuredIn the citing paper
“PI3K/AKT and RAS/ERK signaling pathways also control processes associated with neural excitotoxicity and cell survival [191].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [191]
In the citing paper
“While redox state modulates NMDAR function, activation of synaptic NMDARs strengthens neuronal antioxidant defense mechanisms (Hardingham and Bading, 2010).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Hardingham and Bading, 2010
In the citing paper
“Interestingly, synaptic NMDAR activation boosts GSH, thioredoxin, and peroxiredoxin systems via calcium-mediated signaling involving activation of CREB and inhibition of FOXO (Hardingham and Bading, 2010; Papadia et al., 2008).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Hardingham and Bading, 2010
In the citing paper
“Moreover, GABAergic interneuron-specific deletion of Grin1 has been show to lead to increased ROS levels which are exacerbated by post-weaning social isolation, in association with down-regulation of peroxisome proliferative activated receptor-γ, coactivator 1α (PPARGC1A, also known as PGC-1α), a regulator of mitochondrial energy metabolism and antioxidant defences 78 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [78]
In the citing paper
“Both immunohistochemical and electrophysiological studies have confirmed the existence of extra-synaptic NMDARs, which are not located in the post-synaptic density 68, and are primarily comprised of GluN2B-containing heterotetramers 28, 29.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [68]
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BackgroundFlux-Independent NMDAR Signaling: Molecular Mediators, Cellular Functions, and Complexities
Balderas, P. M. D. O. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123800 · Cited by 42
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“These properties are altered by glutamate receptor composition and location (Lau and Zukin, 2007; Hardingham and Bading, 2010; Paoletti et al., 2013).”
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Alzheimer’s Disease and Protein Kinases
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Self-citationMutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration
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BackgroundMicroglial‐Biomimetic Memantine‐Loaded Polydopamine Nanomedicines for Alleviating Depression
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Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons
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“…to a neuron’s functional response to electrical activity in development and maturity ( Konur and Ghosh, 2005 ; West and Greenberg, 2011 ; Bell and Hardingham, 2011 ), and are totally distinct from the toxic sequelae of excitotoxic Ca 2+ influx ( Hardingham and Bading, 2010 ; Wyllie et al., 2013 ).”
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“mate outside the synaptic cleft, preventing excess glutamate from binding to extra-synaptic NMDA receptors, reducing synaptic efficiency and inducing LTD and excitotoxicity (Hardingham and Bading, 2010), and has been implicated in aging and various neurodegenerative diseases, including AD (Hardingham and Bading, 2010;…”
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“Other studies have shown that severe seizures can induce excitotoxic cell death by activating various intracellular pathways [30], particularly through extrasynaptic NMDA receptors [23, 24].”
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“to limit membrane depolarization and overstimulation of extrasynaptic GluN2B-containing NMDARs, which is shown to cause excitotoxicity [22].”
BackgroundTargeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases
Carles, A., Freyssin, A., Perin-Dureau, F., Rubinstenn, G., & Maurice, T. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073733 · Cited by 47
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“Mechanisms of excitotoxicity can differ depending on the intensity of insult [4,12], although other factors such as synaptic/extrasynaptic location and subunit composition also matter [46,88,89].”
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Vitamin C modulates glutamate transport and NMDA receptor function in the retina
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Glutamate Dehydrogenase as a Neuroprotective Target Against Neurodegeneration
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“There is an ongoing debate about why sustained activation of extrasynaptic N-Methyl-d-aspartate acid receptors (NMDARs) signaling leads to neurotoxicity, but, stimulation of synaptic signaling through NDMARs can contribute to neuroprotection [58, 59].”
Cause or compensation?—Altered neuronal Ca2+ handling in Huntington's disease
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NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content
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“To test this idea, we first examined changes in ERK phosphorylation (pERK), because activation of synaptic NMDARs leads to an increase in pERK, whereas extrasynaptic NMDAR activation decreases pERK levels (Hardingham and Bading, 2010).”
BackgroundMemantine selectively blocks extrasynaptic NMDA receptors in rat substantia nigra dopamine neurons
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“However, recent studies suggest that the subcellular distribution of NMDA receptors may influence their biological action, and some receptor subtypes may be more relevant for neuroprotection than others (Xu et al., 2009; Hardingham and Bading, 2010).”
BackgroundGlutamate as a Neurotransmitter
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The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders
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“In contrast, GluN2B-containing NMDARs are prevailing at peri- and extra synaptic sites [26,27].”
BackgroundAdenosine A2Areceptors facilitate synaptic NMDA currents in CA1 pyramidal neurons
Mouro, F. M., Rombo, D. M., Dias, R. B., Ribeiro, J. A., & Sebastião, A. M. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14497 · Cited by 38
“On the other hand, NMDA receptors are the main mediators of excitotoxicity, whenever there is an excessive and neurotoxic increase in intracellular calcium (Hardingham and Bading, 2010).”
BackgroundInfluentialChen, Y., Wang, Y., Modrusan, Z. D., Sheng, M., & Kaminker, J. S. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0569-14.2014 · Cited by 37
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“Interestingly, the extrasynaptic NMDAR activity that promotes cell death in cultured ischemic neurons has been shown to inhibit ERK phosphorylation, while synaptic NMDAR activity demonstrates the opposite effect through conferring neuroprotection and promoting ERK phosphorylation.(35) On this basis, we can surmise tha…”
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“perisynaptic, if they lie within 100 nm from the PSD (Hardingham and Bading, 2010; Petralia et al., 2010).”
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“primarily the expression of cell death genes (Hardingham and Bading, 2010).”
BackgroundAlbertini, G., Deneyer, L., Ottestad‐Hansen, S., Zhou, Y., Ates, G., Walrave, L., Demuyser, T., Bentea, E., Sato, H., Bundel, D. D., et al. (2018) · Glia · doi:10.1002/glia.23343 · Cited by 37
“…the time frame of microglial activation often correlates to the behavioral changes and minocycline-mediated attenuation of microglial activation and release of cytokines in the cortex and hippocampus can reverse sickness and depressive-like behavior (Henry et al., 2008; Kreisel et al., 2014).”
BackgroundMüller, M., Jacobi, E., Sakimura, K., Malinow, R., & von Engelhardt, J. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0611-4 · Cited by 40
Zinc-mediated Neurotransmission in Alzheimer's Disease: A Potential Role of the GPR39 in Dementia
Rychlik, M., & Młyniec, K. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190704153807 · Cited by 37
Roshanravan, H., Kim, E. Y., & Dryer, S. E. (2016) · Diabetes · doi:10.2337/db16-0209 · Cited by 37
“Excessive activation of CNS NMDA receptors induces Ca overload and oxidative stress, leading to neurodegeneration (47).”
BackgroundZhang, K., Liu, R., Gao, Y., Ma, W., & Shen, W. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s274778 · Cited by 39
Takase, K., Yamamoto, Y., & Yagami, T. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.04.016 · Cited by 40
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Cervantes, M. I., Balderas, P. M. D. O., Gutiérrez-Baños, J. D. J., Orozco‐Ibarra, M., Fernández-Rojas, B., Medina‐Campos, O. N., Espinoza-Rojo, M., Tachiquín, M. E. R., Ortíz-Plata, A., Salazar, M. I., et al. (2013) · Food Chemistry · doi:10.1016/j.foodchem.2013.02.053 · Cited by 36
Peripheral and Central Glutamate Dyshomeostasis in Neurodegenerative Disorders
Onaolapo, A. Y., & Onaolapo, O. J. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666201015161919 · Cited by 37
Nuzzo, T., Mancini, A., Miroballo, M., Casamassa, A., Maio, A. D., Donati, G., Sansone, G., Gaetani, L., Paoletti, F. P., Isidori, A. M., et al. (2021) · Amino Acids · doi:10.1007/s00726-021-02943-7 · Cited by 36
The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics
Wilkie, C. M., Barron, J. C., Brymer, K. J., Barnes, J. R., Nafar, F., & Parsons, M. P. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.661412 · Cited by 35
Seillier, C., Lesept, F., Toutirais, O., Potzeha, F., Blanc, M., & Vivien, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810336 · Cited by 47
“, either synaptic or extrasynaptic compartment, NMDARs can mediate opposite effects [51].”
BackgroundEphB3 signaling propagates synaptic dysfunction in the traumatic injured brain
Perez, E. J., Cepero, M. L., Perez, S. U., Coyle, J. T., Sick, T. J., & Liebl, D. J. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.06.007 · Cited by 35
“In the CCI injured hippocampus, we observed increased levels of the NR2B subunit of the NMDAR in bothWT and EphB3−/− mice, which has been shown to be associated with extra-synaptic NMDARs and the detrimental effects of NMDAR overactivation (Bading et al., 1993; Hardingham and Bading, 2010; Hardingham et al., 2002).”
Dai, H., Xu, M., Lv, J., Ji, X., Zhu, S., Ma, R., Miao, X., & Duan, M. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9391-z · Cited by 35
Wild, A. R., Bollands, M., Morris, P. G., & Jones, S. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.13075 · Cited by 34
Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases
Link, A. S., Zheng, F., & Alzheimer, C. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00032 · Cited by 38
“A widely held concept posits that a proper balance between signals transmitted by synaptic vs. extrasynaptic NMDARs is an essential determinant of neuronal integrity (Hardingham and Bading, 2010).”
BackgroundMolecular Mechanisms of Anesthetic Neurotoxicity: A Review of the Current Literature
Jackson, W. M., Gray, C., Jiang, D., Schaefer, M. L., Connor, C., & Mintz, C. D. (2016) · Journal of Neurosurgical Anesthesiology · doi:10.1097/ana.0000000000000348 · Cited by 35
Kovalenko, M. V., Milnerwood, A. J., Giordano, J. V., Claire, J. S., Guide, J. R., Stromberg, M., Gillis, T., Sapp, E., DiFiglia, M., MacDonald, M. E., et al. (2018) · Journal of Huntington s Disease · doi:10.3233/jhd-170282 · Cited by 34
“Finally, to probe very early synaptic alterations that precede other phenotypes as seen in other HD mouse models [22], we performed acute slice electrophysiology at 2 and 4.”
BackgroundMethodInfluentialScaling Synapses in the Presence of HIV
Green, M. V., Raybuck, J. D., Zhang, X., Wu, M. M., & Thayer, S. A. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2502-2 · Cited by 36
“Another distinction between the GluN2 subtypes is their intracellular C-terminal domains which couple to different downstream signaling pathways [50].”
BackgroundParvalbumin Interneurons Shape Neuronal Vulnerability in Blunt TBI
Chandrasekar, A., Heuvel, F. O., Tar, L., Hagenston, A. M., Palmer, A., Linkus, B., Ludolph, A. C., Huber-Lang, M. S., Boeckers, T. M., Bading, H., et al. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy139 · Cited by 35
Self-citationLeonelli, M., Martins, D. O., & Britto, L. R. (2013) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-012-9904-5 · Cited by 35
“…(NMDA) glutamate receptor signaling may induce nitric oxide synthase (NOS) activity (Garthwaite et al. 1988; Zeevalk and Nicklas 1994; Blute et al. 2000; Garthwaite 2008), oxidative stress (Murphy et al. 1989), and cell death (Hardingham and Bading 2010; Nguyen et al. 2011).”
BackgroundHuang, D., Yu, X., Yu, W.-J., Zhang, X., Liu, C., Liu, H., Sun, Y., & Jiang, Z. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.834962 · Cited by 34
“Coincidentally, extrasynaptic NMDARs have been largely associated with neuronal excitotoxicity (Hardingham and Bading, 2010), and extrasynaptic NMDARs mainly contain NR2B subunits (Petralia, 2012).”
BackgroundCalcium-Associated Proteins in Neuroregeneration
Lisek, M., Tomczak, J., Boczek, T., & Żylińska, L. (2024) · Biomolecules · doi:10.3390/biom14020183 · Cited by 35
“The activation of synaptic NMDARs induces the expression of pro-survival genes, but the activation of extrasynaptic NMDARs initiates the expression of cell death genes [168].”
BackgroundNeural Metabolic Networks: Key Elements of Healthy Brain Function
Madrer, N., Perera, N. D., Uccelli, N. A., Abbondanza, A., Andersen, J. V., Carsana, E. V., Demmings, M. D., Fernandez, R. F., de Fragas, M. G., Gbadamosi, I., et al. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70084 · Cited by 37
“…functions, L-serine plays a crucial role in neurotransmission as the precursor of the obligatory co-agonists of NMDARs, glycine, and D-serine (Maugard et al. 2021), whose levels gate diverse NMDAR functions (Coyle et al. 2020; Sherwood et al. 2021; Hardingham and Bading 2010; Papouin et al. 2012).”
Single-Molecule Imaging Reveals Aβ42:Aβ40 Ratio-Dependent Oligomer Growth on Neuronal Processes
Johnson, R. D., Schauerte, J. A., Chang, C.-C., Wisser, K. C., Althaus, J. C., Carruthers, C. J. L., Sutton, M. A., Steel, D. G., & Gafni, A. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2012.12.051 · Cited by 34
Xu, L., Ren, Z., Chow, F. E., Tsai, R., Liu, T., Rizzolio, F., Boffo, S., Xu, Y., Huang, S., Lippa, C. F., et al. (2017) · Neural Plasticity · doi:10.1155/2017/3270725 · Cited by 33
The role of hypernitrosylation in the pathogenesis and pathophysiology of neuroprogressive diseases
Morris, G., Walder, K. R., Carvalho, A. F., Tye, S. J., Lucas, K., Berk, M., & Maes, M. H. J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.07.017 · Cited by 33
“Perhaps the simplest illustration of a neuroprotective adaptation in response to increasing levels of NO involves the nitrosylation and consequent inhibition of the NDMAR, which acts to reduce NO in a negative feedback loop (Hardingham and Bading, 2010).”
Bonaterra, G. A., Schwendler, A., Hüther, J., Schwarzbach, H., Schwarz, A., Kolb, C., Abdel-Aziz, H., & Kinscherf, R. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00955 · Cited by 34
“…glutamate is considered not only a main reason for the degeneration of neurons and/or cell death as observed in neurodegenerative diseases, but is also a risk factor for mood/anxiety disorders like depression (de Kloet et al., 2005; Grundmann et al., 2010; Hardingham and Bading, 2010).”
BackgroundStem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer’s Disease
Tandon, A., Singh, S. J., & Chaturvedi, R. K. (2018) · BioMed Research International · doi:10.1155/2018/1483791 · Cited by 36
Deleglise, B., Lassus, B., Soubeyre, V., Doulazmi, M., Brugg, B., Vanhoutte, P., & Peyrin, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-29918-1 · Cited by 38
Toffa, D. H., Magnerou, M. A., Kassab, A., Djibo, F. H., & Sow, A. D. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.03.014 · Cited by 33
Ca2+-Dependent Inactivation of GluN2A and GluN2B NMDA Receptors Occurs by a Common Kinetic Mechanism
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Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors
Wang, J. X., Irvine, M. W., Burnell, E. S., Sapkota, K., Thatcher, R. J., Li, M., Simorowski, N., Volianskis, A., Collingridge, G. L., Monaghan, D. T., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14321-0 · Cited by 32
Glutamate and Glutamate Receptors
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From Synapse to Nucleus and Back Again—Communication over Distance within Neurons: Figure 1.
Fainzilber, M., Budnik, V., Segal, R. A., & Kreutz, M. R. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4006-11.2011 · Cited by 34
“Activation of synaptic NMDARs induces the expression of cell survival and plasticity genes, while in contrast, activation of extrasynaptic NMDARs primarily drives expression of cell death genes, linking the pathway to neurodegenerative disorders (Hardingham and Bading, 2010).”
BackgroundKenney, J. W., Sorokina, O., Genheden, M., Sorokin, A., Armstrong, J. D., & Proud, C. G. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2866-14.2015 · Cited by 33
“Bicuculline was chosen as the stimulus because it is known to increase synaptic activity through disinhibition of endogenous neuronal activity present in cultures, whereas direct GluR stimulation of nonsynaptic receptors triggers cell death pathways (Hardingham et al., 2002; Lee et al., 2005; Hardingham and Bading, 20…”
BackgroundMárkus, N. M., Hasel, P., Qiu, J., Bell, K. F. S., Heron, S., Kind, P. C., Dando, O., Simpson, T. I., & Hardingham, G. E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148164 · Cited by 36
“Ca signals induced by membrane depolarization or synaptic activity are generally neuroprotective [43–45], while chronic activation of NMDARs, including extrasynaptic ones, promotes neurodegeneration [46–48].”
BackgroundSelf-citation
Metadata
- Authors
- Hardingham, G. E., & Bading, H.
- Affiliations
- University of Edinburgh (GB)
- Heidelberg University (DE)
- Corresponding author
- Hardingham, Giles E.
- Bading, Hilmar
- Venue
- Nature Reviews Neuroscience
- Published
- 2010-09-15
- Volume
- 11
- Issue
- 10
- Pages
- 682-696
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC2948541
- OpenAlex
- W1966556202
- Cited by
- 1,644
- References
- 167
- Citations by year
- 2026: 83 · 2025: 109 · 2024: 100 · 2023: 111 · 2022: 93 · 2021: 125 · 2020: 112 · 2019: 92 · 2018: 98 · 2017: 99 · 2016: 117 · 2015: 103 · 2014: 128 · 2013: 111 · 2012: 87
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Alexander von Humboldt-Stiftung
- Wellcome Trust (94018, 087491, 088156)
- Deutsche Forschungsgemeinschaft
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- NMDA receptor, synaptic NMDA receptors, extrasynaptic NMDA receptors, neuroprotection, neuronal cell death, intracellular signaling, ischemia, Huntington's disease, neurodegenerative diseases, neuroprotective therapy
- MeSH terms
- Animals, Humans, Synapses, Signal Transduction, Gene Expression, Receptors, N-Methyl-D-Aspartate, Cell Death, Oxidative Stress, Neuroprotective Agents, Neurodegenerative Diseases
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