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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Synaptic NMDAR transmission promotes cell survival, whereas extrasynaptic NMDARs promote cell death through p38MAPK inhibition and activation, respectively.
“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]
The ‘NMDAR paradox’ section says synaptic NMDAR signalling promotes neuronal survival whereas extrasynaptic signalling promotes death. ‘Calpain activation and STEP cleavage’ identifies p38 activation as an extrasynaptic pro-death pathway, but does not support synaptic p38 inhibition as the survival mechanism; it notes that neuroprotective synaptic activity can also activate p38. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAugmented release of glutamate from astrocytes has been shown to decrease brain-derived neurotrophic factor and increase excitotoxicity.
“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
The ‘Extrasynaptic NMDARs in ischaemic stroke’ section reports that glutamate efflux arising mainly from reversed astrocytic uptake causes excitotoxicity in neuron–astrocyte co-cultures. The ‘Induction of survival genes’ section identifies BDNF as a target of protective synaptic NMDAR signalling, but does not show that increased astrocytic glutamate release decreases BDNF. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPI3K/AKT and RAS/ERK signaling pathways also control processes associated with neural excitotoxicity and cell survival.
“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]
Redox state modulates NMDAR function, while activation of synaptic NMDARs strengthens neuronal antioxidant defense mechanisms.
“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
Synaptic NMDAR activation boosts glutathione, thioredoxin, and peroxiredoxin systems via calcium-mediated signaling involving activation of CREB and inhibition of FOXO.
“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
GABAergic interneuron-specific deletion of Grin1 leads to increased ROS levels which are exacerbated by post-weaning social isolation, in association with down-regulation of PPARGC1A/PGC-1α.
“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]
Extra-synaptic NMDARs exist, are not located in the post-synaptic density, and are primarily comprised of GluN2B-containing heterotetramers.
“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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NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
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InfluentialInflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond
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BackgroundSynaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
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BackgroundNeuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review)
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“2) (63,83).”
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Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis
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Inflammation, glutamate, and glia: a trio of trouble in mood disorders
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Astrocyte-neuron metabolic cooperation shapes brain activity
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Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders
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“…response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression, enhances antioxidant defense, and provides neuroprotection, whereas extrasynaptic NMDAR stimulation does the opposite (Hardingham et al., 2002; Hardingham and Bading, 2010; Figure 1B).”
InfluentialThe Role of NMDA Receptors in Alzheimer’s Disease
Liu, J., Chang, L., Song, Y., Li, H., & Wu, Y. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00043 · Cited by 535 · see citing works
“Furthermore, taking into account the fact that extrasynaptic GluN2B-containing NMDARs have been associated with excitotoxicity in AD (Hardingham and Bading, 2010), the use of a selective GluN2B subunit antagonists might be an interesting strategy to prevent synaptic dysfunction in AD.”
BackgroundSuberbielle, E., Sanchez, P. E., Kravitz, A. V., Wang, X., Ho, K., Eilertson, K., Devidze, N., Kreitzer, A. C., & Mucke, L. (2013) · Nature Neuroscience · doi:10.1038/nn.3356 · Cited by 487 · see citing works
Targeting glutamate signalling in depression: progress and prospects
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Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders
Brandebura, A. N., Paumier, A., Onur, T. S., & Allen, N. J. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00641-1 · Cited by 427 · see citing works
Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2015) · Annual Review of Medicine · doi:10.1146/annurev-med-053013-062946 · Cited by 422 · see citing works
“Of note, synaptic and extrasynaptic NMDA receptors [see sidebar, N-Methyl-DAspartate (NMDA) Receptors] have opposing effects on synaptic plasticity, promoting or reducing synaptic strength, respectively (36).”
BackgroundPittenger, C., Bloch, M. H., & Williams, K. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.09.006 · Cited by 426 · see citing works
“…above, the glutamate transporters play a critical role in terminating excitatory neurotransmission and in regulating extrasynaptic glutamate levels, limiting the activation of extrasynaptic neurotransmitter receptors and consequent excitotoxicity (Danbolt, 2001; Hardingham & Bading, 2010).”
BackgroundInfluentialRapid-acting glutamatergic antidepressants: the path to ketamine and beyond
Krystal, J. H., Sanacora, G., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.03.026 · Cited by 406 · see citing works
“This subunit is an important component of the extrasynaptic NMDA receptors (102).”
BackgroundDiversity in NMDA Receptor Composition
Sanz-Clemente, A., Nicoll, R. A., & Roche, K. W. (2012) · The Neuroscientist · doi:10.1177/1073858411435129 · Cited by 397 · see citing works
“Whereas the activation of synaptic NMDARs triggers intracellular cascades promoting cell survival, the entry of calcium through extrasynaptic NMDARs leads to neuronal death via mitochondrial dysfunction (a process known as excitotoxicity) (Hardingham and Bading 2010).”
BackgroundNuclear calcium signalling in the regulation of brain function
Bading, H. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3531 · Cited by 374 · see citing works
“Marchenko, S. M., Yarotskyy, V., Kovalenko, T. N., Kostyuk, P. G. & Thomas, R. C. Spontaneously active and InsP3-activated ion channels in cell nuclei from rat cerebellar Purkinje and granule neurones.”
BackgroundInfluentialSelf-citationKanmani, S., & Koo, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207551 · Cited by 381 · see citing works
“The increasing glutamatergic neurotoxicity is mainly through the differential activation of synaptic versus extrasynaptic N-methyl-D-asparate (NMDA) receptors [47,48].”
BackgroundCalcium signalling remodelling and disease
Berridge, M. J. (2012) · Biochemical Society Transactions · doi:10.1042/bst20110766 · Cited by 391 · see citing works
Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases
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Calcium signaling and molecular mechanisms underlying neurodegenerative diseases
Pchitskaya, E. I., Александровна, П. Е., & Борисович, Б. И. (2017) · Cell Calcium · doi:10.1016/j.ceca.2017.06.008 · Cited by 346 · see citing works
“Activation of synaptic NMDARs is required for synaptic plasticity and drives LTP generation, but sustained activation of NMDARs can cause subsequent calcium overload and toxicity (Hardingham and Bading, 2010).”
BackgroundThe ASD Living Biology: from cell proliferation to clinical phenotype
Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0056-y · Cited by 333 · see citing works
“PI3K/ AKT and RAS/ERK signaling pathways also control processes associated with neural excitotoxicity and cell survival [191].”
Overview of glutamatergic neurotransmission in the nervous system
Niciu, M. J., Kelmendi, B., & Sanacora, G. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.08.008 · Cited by 335 · see citing works
“Finally, glutamatergic neurotoxicity is increasingly thought to be mediated by the differential activation of extrasynaptic relative to synaptic NMDA receptors (Hardingham & Bading, 2010; Hardingham et al., 2002; Ivanov et al., 2006; Leveille et al., 2008; Vanhoutte & Bading, 2003; Xu et al., 2009).”
Raymond, L. A., André, V. M., Cepeda, C., Gladding, C. M., Milnerwood, A. J., & Levine, M. S. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.052 · Cited by 319 · see citing works
“…and activation of cell death signaling p38 and c-Jun N-terminal Kinase MitogenActivated Protein Kinases (JNK MAPKs) (Hardingham et al., 2002; Cao et al., 2004; Ivanov et al., 2006; Leveille et al., 2008; Soriano et al., 2008; Wahl et al., 2009; Xu et al., 2009; Hardingham and Bading, 2010).”
BackgroundGoing the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases
Armada‐Moreira, A., Gomes, J. I., Pina, C. C., Savchak, O. K., Gonçalves‐Ribeiro, J., Rei, N., Pinto, S., Morais, T. P., Martins, R. S., Ribeiro, F. F., et al. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00090 · Cited by 323 · see citing works
Synaptic plasticity in depression: Molecular, cellular and functional correlates
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Dendritic Tau in Alzheimer’s Disease
Ittner, A., & Ittner, L. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.003 · Cited by 278 · see citing works
Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
Hardingham, G. E., & Do, K. Q. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.19 · Cited by 304 · see citing works
Self-citationNMDA receptors in nervous system diseases
Zhou, Q., & Sheng, M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.03.030 · Cited by 293 · see citing works
“…2002;HardinghamandBading, 2010). ba Localization Model Sub Stimulating synaptic NMDARs activates cAMP response elementbinding protein (CREB) signaling and promotes survival, while activation of extrasynaptic NMDARs attenuates CREB signaling and promotes cell death (Hardingham and Bading, 2010).”
InfluentialFieblinger, T., Graves, S. M., Sebel, L. E., Alcacer, C., Plotkin, J. L., Gertler, T. S., Chan, C. S., Heiman, M., Greengard, P., Cenci, M. A., et al. (2014) · Nature Communications · doi:10.1038/ncomms6316 · Cited by 293 · see citing works
Uzdensky, A. B. (2019) · APOPTOSIS · doi:10.1007/s10495-019-01556-6 · Cited by 293 · see citing works
Dysfunction of NMDA receptors in Alzheimer’s disease
Zhang, Y., Li, P., Feng, J., & Wu, M. (2016) · Neurological Sciences · doi:10.1007/s10072-016-2546-5 · Cited by 282 · see citing works
“…can also be taken up by the presynaptic terminal or astrocytes by their respective transporters Activation of synaptic NMDARs mediates synaptic plasticity and is thought to be beneficial for neurons, whereas prolonged activation of NMDARs with subsequent overload of Ca 2 ? entry is deleterious [32].”
BackgroundSaxena, S., Roselli, F., Singh, K., Leptien, K., Julien, J.-P., Gros-Louis, F., & Caroni, P. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.027 · Cited by 275 · see citing works
“Furthermore, excitability and synaptic calcium entry have been related to neuroprotective signaling (Hardingham and Bading, 2010).”
HDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory
Sando, R., Gounko, N., Pieraut, S., Liao, L., Yates, J., & Maximov, A. (2012) · Cell · doi:10.1016/j.cell.2012.09.037 · Cited by 274 · see citing works
Luhmann, H. J., Sinning, A., Yang, J., Reyes‐Puerta, V., Stüttgen, M. C., Kirischuk, S., & Kilb, W. (2016) · Frontiers in Neural Circuits · doi:10.3389/fncir.2016.00040 · Cited by 275 · see citing works
“But also other survival-promoting pathways can be activated depending on the pattern of electrical activity or the site of calcium entry (for review see Hardingham and Bading, 2010; Bell and Hardingham, 2011).”
BackgroundSite-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice
Ittner, A., Chua, S. W., Bertz, J., Volkerling, A., van der Hoven, J., Gladbach, A., Przybyla, M., Bi, M., van Hummel, A., Stevens, C. H., et al. (2016) · Science · doi:10.1126/science.aah6205 · Cited by 263 · see citing works
The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders
Stone, T. W., & Darlington, L. G. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12230 · Cited by 272 · see citing works
“The overall amounts and ratio between the different glutamate receptor subunits is increasingly considered to be critical in synaptic function, plasticity and neurodegeneration (Hardingham and Bading, 2011).”
BackgroundQiu, J., Tan, Y.-W., Hagenston, A. M., Martel, M., Kneisel, N., Skehel, P., Wyllie, D. J. A., Bading, H., & Hardingham, G. E. (2013) · Nature Communications · doi:10.1038/ncomms3034 · Cited by 267 · see citing works
“It will also be of interest to determine whether and how mitochondrial Ca 2 þ uptake contributes to the differential effects of synaptic versus extrasynaptic NMDAR activity 28,38 .”
Self-citationSteullet, P., Cabungcal, J. H., Monin, A., Dwir, D., O'Donnell, P., Cuenod, M., & Do, K. Q. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2014.06.021 · Cited by 262 · see citing works
“Interestingly, synaptic NMDAR activation boosts GSH, thioredoxin, and peroxiredoxin systems via calcium-mediated signaling involving activation of CREB and inhibition of FOXO (Papadia et al., 2008; Hardingham and Bading, 2010).”
Influence of GluN2 subunit identity on NMDA receptor function
Wyllie, D. J. A., Livesey, M. R., & Hardingham, G. E. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.01.016 · Cited by 260 · see citing works
“The specific sub-cellular localisation of GluN2A and GluN2Bcontaining NMDARs within the adult forebrain has been of considerable interest given the differing roles of synaptic and extrasynaptic NMDARs in signalling to neuronal survival and death (reviewed in Hardingham and Bading, 2010).”
BackgroundInfluentialSelf-citationHaroon, E., Fleischer, C. C., Felger, J. C., Chen, X., Woolwine, B. J., Patel, T., Hu, X. P., & Miller, A. H. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.206 · Cited by 250 · see citing works
“1,32 11 Increased glutamate in these brain regions in turn correlated with depressive symptoms including anhedonia and fatigue.”
Physiology and Pathology of Calcium Signaling in the Brain
Kawamoto, E. M., Vivar, C., & Camandola, S. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00061 · Cited by 250 · see citing works
“Growing evidence suggest that physiological levels of synaptic NMDA receptor activation may enhance resistance to trauma and promote survival of various neuronal types (Hardingham and Bading, 2010).”
BackgroundSanacora, G., & Banasr, M. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.03.032 · Cited by 239 · see citing works
“Excessive activation of extrasynaptic to synaptic NMDA receptors has been linked to various forms of excitotoxicity, and has been implemented in the pathophysiology of multiple neurodegenerative disorders (57).”
BackgroundCortical layers: Cyto-, myelo-, receptor- and synaptic architecture in human cortical areas
Palomero‐Gallagher, N., & Zilles, K. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2017.08.035 · Cited by 239 · see citing works
Nakajima, A., & Ohizumi, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143380 · Cited by 239 · see citing works
Inflammation-Associated Co-morbidity Between Depression and Cardiovascular Disease
Halaris, A. (2016) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2016_28 · Cited by 233 · see citing works
d-serine levels in Alzheimer’s disease: implications for novel biomarker development
Madeira, C., Lourenco, M. V., Vargas-Lopes, C., Suemoto, C. K., Brandão, C. O., Reis, T., Leite, R. E. P., Laks, J., Jacob-Filho, W., Pasqualucci, C. A., et al. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.52 · Cited by 233 · see citing works
Molecular Mechanisms of Glutamate Toxicity in Parkinson’s Disease
Wang, J., Wang, F., Mai, D., & Qu, S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.585584 · Cited by 228 · see citing works
The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System
Zeldich, E., Chen, C.-D., Colvin, T. A., Bove‐Fenderson, E., Liang, J. J., Zhou, T. B. T., Harris, D. A., & Abraham, C. R. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.567321 · Cited by 225 · see citing works
“Furthermore, synaptic NMDA receptor activity promotes sustained activation of the Akt pathway, leading to the phosphorylation and nuclear export of FoxO and subsequent inactivation of FoxO target genes, such as thioredoxin-interacting protein (Txnip) (82, 83).”
BackgroundrTMS enhances BDNF–TrkB signaling in both brain and lymphocyte
Wang, H.-Y., Crupi, D., Liu, J.-J., Stucky, A., Cruciata, G., Rocco, A. D., Friedman, E., Quartarone, A., & Ghilardi, M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2125-11.2011 · Cited by 213 · see citing works
“…to neuropsychiatric disorders There is increasing evidence that NMDA-dependent cortical plasticity is altered in many neuropsychiatric illnesses (Hardingham and Bading, 2010), including Alzheimer disease (Wang et al., 2009), Parkinson’s disease (Meoni et al., 1999), dystonia (Akopian et al.,…”
BackgroundRevisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions
Jarrahi, A., Braun, M., Ahluwalia, M., Gupta, R. V., Wilson, M., Munie, S., Ahluwalia, P. K., Vender, J. R., Vale, F. Ĺ., Dhandapani, K. M., et al. (2020) · Biomedicines · doi:10.3390/biomedicines8100389 · Cited by 226 · see citing works
Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration
Baudry, M., & Bi, X. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.01.007 · Cited by 223 · see citing works
Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.05.010 · Cited by 219 · see citing works
Neuronal networks provide rapid neuroprotection against spreading toxicity
Samson, A. J., Robertson, G. R., Zagnoni, M., & Connolly, C. N. (2016) · Scientific Reports · doi:10.1038/srep33746 · Cited by 218 · see citing works
Delineating the <i>GRIN1</i> phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy
Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schütz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002740 · Cited by 200 · see citing works
“In contrast to GluN2/3 subunits, which each have specific spatial and temporal expression patterns throughout the CNS, GluN1 encoded by GRIN1 is a ubiquitous component of the receptor.(4,5) Mutations of the NMDAR subunits are associated with a variety of different neurodevelopmental phenotypes,(3) including intellectu…”
BackgroundGRIN2B mutations in west syndrome and intellectual disability with focal epilepsy
Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hörtnagel, K., et al. (2013) · Annals of Neurology · doi:10.1002/ana.24073 · Cited by 212 · see citing works
Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia
Berridge, M. J. (2013) · Prion · doi:10.4161/pri.21767 · Cited by 209 · see citing works
Takahashi, K., Foster, J. B., & Lin, C. G. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1937-8 · Cited by 213 · see citing works
“The activation of synaptic NMDA receptors promotes cell survival while extrasynaptic NMDA receptor activation promotes cell death which is termed excitotoxicity (for review see: [100, 101]).”
BackgroundKETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID‐ACTING ANTIDEPRESSANTS
Abdallah, C. G., Adams, T. G., Kelmendi, B., Esterlis, I., Sanacora, G., & Krystal, J. H. (2016) · Depression and Anxiety · doi:10.1002/da.22501 · Cited by 206 · see citing works
“, reduced dendritic arborization, decreased dendritic length, synaptic loss, and neuronal death).[52] As such, blockage of extrasynaptic NMDA receptors promotes synaptogenesis.”
Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors
Mota, S. I., Ferreira, I. L., & Rego, A. C. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.08.013 · Cited by 206 · see citing works
“Interestingly, extrasynaptic NMDARs have been largely associated with NMDARs excitotoxicity in AD (Hardingham and Bading, 2010).”
InfluentialMorgan, T. E., Davis, D. A., Iwata, N., Tanner, J. A., Snyder, D., Ning, Z., Kam, W. W.-Y., Hsu, Y., Winkler, J. W., Chen, J., et al. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1002973 · Cited by 204 · see citing works
“…the possibility that nPM could be neurotoxic through glutamatergic mechanisms, particularly N-methyl-d-aspartic acid (NMDA) receptors, which are implicated in hypoxic-ischemic neuronal damage and excitotoxic cell death (Hardingham and Bading 2010; Lynch and Guttmann 2002; Mizuno et al. 2008).”
BackgroundNMDA Receptors in the Central Nervous System
Hansen, K. B., Yi, F., Perszyk, R. E., Menniti, F. S., & Traynelis, S. F. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7321-7_1 · Cited by 206 · see citing works
Current view on the functional regulation of the neuronal K+-Cl− cotransporter KCC2
Medina, I., Friedel, P., Rivera, C., Kahle, K. T., Kourdougli, N., Uvarov, P., & Pellegrino, C. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00027 · Cited by 203 · see citing works
“At these doses, NMDA triggers several neurotoxic signaling cascades (Hardingham et al., 2002; Ivanov et al., 2006), reviewed by Medina (2007) and Hardingham and Bading (2010).”
BackgroundZhou, X., Hollern, D. P., Liao, J., Andrechek, E. R., & Wang, H. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.82 · Cited by 200 · see citing works
“This is in contrast to the prevailing hypothesis, emphasizing that ex-NMDAR contributes to excitotoxicity by shutting off pro-survival signaling.(7,8,28) By carefully controlling NMDAR activation at different locations, we showed that blocking syn-NMDAR ablated cell death after”
BackgroundResultMechanisms of specificity in neuronal activity-regulated gene transcription
Lyons, M. R., & West, A. E. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.05.003 · Cited by 199 · see citing works
“Different pools of NMDARs differentially regulate transcription—The subunit composition of NMDARs has a strong effect on their function (Hardingham and Bading, 2010).”
BackgroundMechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function
Gladding, C. M., & Raymond, L. A. (2011) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2011.05.001 · Cited by 197 · see citing works
Neuroimmune Function and the Consequences of Alcohol Exposure
Crews, F. T. (2015) · Alcohol research · doi:10.35946/arcr.v37.2.15 · Cited by 200 · see citing works
“, N-methyl-d-aspartate [NMDA] receptors) and excitotoxicity, resulting in either rapid or delayed neuronal death, which is associated with reduced CREB (Hardingham and Bading 2010).”
A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease
Ambrosi, G., Cerri, S., & Blandini, F. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-013-1149-z · Cited by 195 · see citing works
Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice
Dubal, D. B., Zhu, L., Sanchez, P. E., Worden, K., Broestl, L., Johnson, E. C. B., Ho, K., Yu, G.-Q., Kim, D., Bétourné, A., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.5791-12.2015 · Cited by 197 · see citing works
“Klotho elevation enriches GluN2B in postsynaptic densities of hAPP mice The biological consequences of NMDAR stimulation are critically dependent on whether the receptors are located in synaptic or extrasynaptic sites (Hardingham and Bading, 2010).”
BackgroundPham, T. H., & Gardier, A. M. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.02.017 · Cited by 186 · see citing works
d-glutamate and Gut Microbiota in Alzheimer’s Disease
Chang, C.-H., Lin, C.-H., & Lane, H.-Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082676 · Cited by 191 · see citing works
“Finally, these effects may contribute to the inhibition of apoptosis and promotion of cell survival [72,73].”
BackgroundAstrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway
Jimenez-Blasco, D., Santofimia-Castaño, P., Gonzalez, A., Almeida, A., & Bolaños, J. P. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2015.49 · Cited by 196 · see citing works
“tive oxygen species (ROS) responsible for oxidative damage and neurodegeneration.(1,2) To defend themselves against”
BackgroundHijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion
Li, L., & Hanahan, D. (2013) · Cell · doi:10.1016/j.cell.2013.02.051 · Cited by 194 · see citing works
Singh, A. K., Kashyap, M. P., Tripathi, V., Singh, S., Garg, G., & Rizvi, S. I. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0129-3 · Cited by 195 · see citing works
Karpova, A., Mikhaylova, M., Bera, S., Bär, J., Reddy, P. P., Behnisch, T., Rankovic, V., Spilker, C., Bethge, P., Şahin, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.02.002 · Cited by 194 · see citing works
“Most importantly, extrasynaptic NMDAR signaling has no effect on ERK1/2 phosphorylation, whereas sustained synaptic NMDAR signaling triggers the nuclear import of active ERK1/2 (Ivanov et al., 2006; Kim et al., 2005; Hardingham and Bading, 2010).”
InfluentialMitochondria: hub of injury responses in the developing brain
Hagberg, H., Mallard, C. E., Rousset, C. I., & Thornton, C. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70261-8 · Cited by 194 · see citing works
STING orchestrates the neuronal inflammatory stress response in multiple sclerosis
Woo, M. S., Mayer, C., Binkle-Ladisch, L., Sonner, J. K., Rosenkranz, S. C., Shaposhnykov, A., Rothammer, N., Tsvilovskyy, V., Lorenz, S., Raich, L., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.031 · Cited by 193 · see citing works
Psychiatric Disorders: Diagnosis to Therapy
Krystal, J. H., & State, M. W. (2014) · Cell · doi:10.1016/j.cell.2014.02.042 · Cited by 191 · see citing works
Mithaiwala, M. N., Santana-Coelho, D., Porter, G. A., & O’Connor, J. C. (2021) · Cells · doi:10.3390/cells10061548 · Cited by 190 · see citing works
Extracellular glutamate: functional compartments operate in different concentration ranges
Moussawi, K., Riegel, A., Nair, S., & Kalivas, P. W. (2011) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2011.00094 · Cited by 184 · see citing works
“Electron microscopy reveals that akin to synaptic NMDAr, approximately 80% of the extrasynaptic NMDAr are localized to points of near contact between adjacent processes (Hardingham and Bading, 2010; Petralia et al., 2010).”
BackgroundMAGUKs, Synaptic Development, and Synaptic Plasticity
Zheng, C.-Y., Seabold, G. K., Hořák, M., & Petralia, R. S. (2011) · The Neuroscientist · doi:10.1177/1073858410386384 · Cited by 188 · see citing works
Gąsiorowska, A., Wydrych, M., Drapich, P., Zadrożny, M., Steczkowska, M., Niewiadomski, W., & Niewiadomska, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.654931 · Cited by 192 · see citing works
Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use
Taylor, C. P., Traynelis, S. F., Siffert, J. O., Pope, L. E., & Matsumoto, R. R. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.010 · Cited by 187 · see citing works
The neuropathobiology of multiple sclerosis
Woo, M. S., Engler, J. B., & Friese, M. A. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00823-z · Cited by 194 · see citing works
“Suppression of the TCA might be regulated on a transcriptional level, which was demonstrated in an independent study that performed neuronal translatome profiling at a similar disease stage in EAE 104 .”
The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders
O'Donovan, S. M., Sullivan, C. R., & McCullumsmith, R. E. (2017) · Schizophrenia · doi:10.1038/s41537-017-0037-1 · Cited by 184 · see citing works
“It results in non-specific glutamate binding, activation of glutamate receptors and “runaway” excitatory transmission that may eventually result in neurotoxic cell death.(8,9) Thus, glutamate clearance is an essential and highly regulated process controlled by a family of transporter proteins that constitute at least…”
BackgroundInflammation in schizophrenia: A question of balance
Leza, J. C., García‐Bueno, B., Bioque, M., Arango, C., Parellada, M., Kim, Q., O’Donnell, P., & Bernardo, M. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.05.014 · Cited by 183 · see citing works
Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia
Berridge, M. J. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1806-z · Cited by 181 · see citing works
“The role of enhanced oxidation in driving these phenotypic alterations of the inhibitory interneurons is also consistent with studies of the changes in the antioxidant mechanisms that have been described in neurodegenerative disorders (Hardingham and Bading 2010) including schizophrenia.”
ResultTranssynaptic modulation of kainate receptor functions by C1q-like proteins
Matsuda, K., Budisantoso, T., Mitakidis, N., Sugaya, Y., Miura, E., Kakegawa, W., Yamasaki, M., Konno, K., Uchigashima, M., Abe, M., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.001 · Cited by 180 · see citing works
“While AMPA receptors mediate fast neurotransmission at the postsynaptic site, NMDA receptors regulate synaptic plasticity and cell survival at postsynaptic and extrasynaptic sites, respectively 3 (Hardingham and Bading, 2010).”
- 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 › 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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