The DOI matches its Crossref record; 168 of the 168 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A synaptic model of memory: long-term potentiation in the hippocampus
Bliss, T. V. P., & Collingridge, G. L. (1993) · Nature · doi:10.1038/361031a0 · Cited by 11,566
Glutamate neurotoxicity and diseases of the nervous system
Choi, D. W. (1988) · Neuron · doi:10.1016/0896-6273(88)90162-6 · Cited by 8,188
Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders
Epstein, F. H., Lipton, S. A., & Rosenberg, P. A. (1994) · New England Journal of Medicine · doi:10.1056/nejm199403033300907 · Cited by 2,676
Transcriptional regulation by the phosphorylation-dependent factor CREB
Mayr, B., & Montminy, M. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35085068 · Cited by 2,587
Glutamate and the pathophysiology of hypoxic–ischemic brain damage
Rothman, S. M., & Olney, J. W. (1986) · Annals of Neurology · doi:10.1002/ana.410190202 · Cited by 2,428
St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jäger, S., Handschin, C., Zheng, K., Lin, J., Yang, W., et al. (2006) · Cell · doi:10.1016/j.cell.2006.09.024 · Cited by 2,233
Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain
Ikonomidou, C., Bosch, F., Miksa, M., Bittigau, P., Vöckler, J., Dikranian, K., Tenkova, T. I., Stefovska, V., Turski, L., & Olney, J. W. (1999) · Science · doi:10.1126/science.283.5398.70 · Cited by 2,055
Phosphorylated CREB binds specifically to the nuclear protein CBP
Chrivia, J. C., Kwok, R. P. S., Lamb, N., Hagiwara, M., Montminy, M. R., & Goodman, R. H. (1993) · Nature · doi:10.1038/365855a0 · Cited by 2,052
Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., & Greenberg, M. E. (1999) · Science · doi:10.1126/science.286.5443.1358 · Cited by 1,908
Brain Lesions, Obesity, and Other Disturbances in Mice Treated with Monosodium Glutamate
Olney, J. (1969) · Science · doi:10.1126/science.164.3880.719 · Cited by 1,885
Flagged first, then by citations
Research works printed but not linked: 1
- Soriano, F. X., Leveille, F., Papadia, S., Bell, K. F. & Hardingham, G. E. Neuronal activity controls the antagonistic balance between PGC-1α and SMRT in regulating antioxidant defences. Antioxid. Redox Signal. (in the press).
Cited by
Sorted by citations
Items 901–1,000 of 1,001
Yap, Y. W., Llanos, R. M., Fontaine, S. L., Cater, M. A., Beart, P. M., & Cheung, N. S. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1666-2 · Cited by 16
“The well-being of neurons in the mammalian CNS is dependent on the balance of the activities of the survivalpromoting synaptic GluRs and the death-inducing extrasynaptic GluRs [52].”
BackgroundModulation of GluN3A Expression in Huntington Disease
Wesseling, J. F., & Pérez‐Otaño, I. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3953 · Cited by 16
Yan, L., Imbrosci, B., Zhang, W., Neubacher, U., Hatt, H. H., Eysel, U. T., & Mittmann, T. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhr318 · Cited by 17
“Here, the activity of synaptically located NMDARs seem to be neuroprotective, while extrasynaptic NMDARs may promote cell death (for review, see Hardingham and Bading 2010).”
BackgroundPeptidergic Drugs For the Treatment of Traumatic Brain Injury
Alvarez, X. A., Figueroa, J., & Muresanu, D. F. (2013) · Future Neurology · doi:10.2217/fnl.12.95 · Cited by 17
Modulation of NMDA channel gating by Ca2+ and Cd2+ binding to the external pore mouth
Tu, Y., Yang, Y., & Kuo, C. (2016) · Scientific Reports · doi:10.1038/srep37029 · Cited by 16
Berlin, S., & Isacoff, E. Y. (2017) · Neuromethods · doi:10.1007/978-1-4939-7228-9_10 · Cited by 17
Long Term Depression in Rat Hippocampus and the Effect of Ethanol during Fetal Life
Pierrefiche, O. (2017) · Brain Sciences · doi:10.3390/brainsci7120157 · Cited by 16
“Indeed, in adult animals, GluN2B-containing receptors predominate at peri- and extrasynaptic sites [48,49].”
BackgroundHuntington’s disease: novel therapeutic perspectives hanging in the balance
Saavedra, A., Barriga, G. G.-D., Pérez‐Navarro, E., & Alberch, J. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1465930 · Cited by 18
“regulator of the balance between survival-promoting synaptic and death-inducing extrasynaptic [12,20,22] NMDARs, and that it promotes neuroprotection by reducing toxic NMDAR signaling [103].”
BackgroundNewman, S. D., Cheng, H., Kim, D., Martin, A. M. S., Dydak, U., Dharmadhikari, S., Hetrick, W. P., & O’Donnell, B. F. (2019) · Brain Imaging and Behavior · doi:10.1007/s11682-019-00165-w · Cited by 15
Senescent neurophysiology: Ca2+ signaling from the membrane to the nucleus
Foster, T. C. (2019) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2019.107064 · Cited by 16
Liu, H., Li, S., Yang, C., Jia, H., Gu, Z., Tu, X., Tian, S., Liu, J., Li, G., & Ma, Y. (2020) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2020.101852 · Cited by 16
Interplay between Gating and Block of Ligand-Gated Ion Channels
Phillips, M. B., Nigam, A., & Johnson, J. W. (2020) · Brain Sciences · doi:10.3390/brainsci10120928 · Cited by 19
System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration
Brabec, J. L., Lara, M. K., Tyler, A. L., & Mahoney, J. M. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.625246 · Cited by 18
“…high level of glutamate release by astrocytes leads to an increase in extra-synaptic glutamate signaling and excitotoxicity (Sattler et al., 2000; Hardingham and Bading, 2010; Parsons and Raymond, 2014; Wang and Reddy, 2016), which is hypothesized to both induce ER stress (Sokka et al., 2007;…”
BackgroundNakanishi, N., Kang, Y., Tu, S., McKercher, S. R., Masliah, E., & Lipton, S. A. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0651-1 · Cited by 16
“The hippocampus, including the molecular layer of the dentate gyrus and pyramidal layer of the CA1 region, was analyzed quantitatively for each antibody label.”
The transmembrane transporter domain of glutamate transporters is a process tip localizer
Hayashi, M. K., & Yasui, M. (2015) · Scientific Reports · doi:10.1038/srep09032 · Cited by 16
Li, L., Li, Z., Cao, Y., Fan, D., Chui, D., & Guo, X. (2016) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2016.3306 · Cited by 17
“NMDARs with different subunits and localization trigger different signaling pathways (13), which play different roles in synaptic plasticity, learning and memory, cell survival, excitotoxicity and cell death (6,14,15).”
NMDA Receptor Signaling Mediates cFos Expression via Top2β-Induced DSBs in Glioblastoma Cells
Lutz, H., Nguyen, T. A., Joswig, J., Rau, K., & Laube, B. (2019) · Cancers · doi:10.3390/cancers11030306 · Cited by 16
“NMDAR-signaling acts by activating two major downstream signaling pathways: The Ca2+/calmodulin kinase (CaMK-II/IV) pathway and the mitogen-activated protein kinase (MAPK) pathway [7].”
BackgroundFreire‐Cobo, C., Sierra‐Paredes, G., Freire, M., & Sierra‐Marcuño, G. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9558-9 · Cited by 17
Vandresen-Filho, S., Severino, P. C., Constantino, L. C., Martins, W. C., Molz, S., Dal-Cim, T., Bertoldo, D. B., Silva, F. R. M. B., & Tasca, C. I. (2015) · Neurotoxicity Research · doi:10.1007/s12640-014-9496-6 · Cited by 17
“As discussed earlier, one possible explanation for these protective effects could rely on the fact that low doses of NMDA may lead to synaptic NMDAR activation and induction of pro-survival pathways (Hardingham and Bading 2010).”
BackgroundInfluentialChen, S., Liang, T., Xue, T., Xue, S., & Xue, Q. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.658123 · Cited by 15
Huber, N., Hoffmann, D. B., Giniatullina, R., Rostalski, H., Leskelä, S., Takalo, M., Natunen, T., Solje, E., Remes, A. M., Giniatullin, R. A., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105584 · Cited by 17
The dark side of synaptic proteins in tumours
Li, J., Xu, Y., Zhu, H., Wang, Y., Li, P., & Wang, D. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01863-x · Cited by 15
“These genes further modulate the gene expression profile of the neuron and exert significant influence on neuronal growth, proliferation, survival, migration and synaptic plasticity [57, 58].”
BackgroundLiao, W., Wen, Y., Yang, S., Duan, Y., & Liu, Z. (2023) · Medicine · doi:10.1097/md.0000000000035490 · Cited by 15
“[61,73] Bcl-2 family proteins are a class of important molecules that regulate apoptosis, some of which have anti-apoptotic effects, such as bcl-2, bcl-xL, etc, and some have pro-apoptotic effects, such as bax, bak, etc. Bcl-2 family proteins can regulate apoptotic cascade by affecting the…”
BackgroundTarasenko, A. S., Krupko, O., & Himmelreich, N. H. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.07.021 · Cited by 15
Debernard, K. A. B., Mathisen, G. H., & Paulsen, R. E. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.04.002 · Cited by 15
“ERK activity can be regulated by NMDA receptors (Ivanov et al., 2006; Krapivinsky et al., 2003), and ERK can phosphorylates CREB after calcium stimulus (Hardingham and Bading, 2010).”
BackgroundTargeting Oxidative Stress in Stroke
Bach, A. (2017) · Springer series in translational stroke research · doi:10.1007/978-3-319-45345-3_8 · Cited by 15
Kumar, M., John, M., Mayadevi, M., James, J., & Omkumar, R. V. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134343 · Cited by 15
Polli, F. S., & Kohlmeier, K. A. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107744 · Cited by 15
The role of glutamate in the pathogenesis of multiple sclerosis
Kuzmina, U. S., Зайнуллина, Л. Ф., Вахитов, В. А., Bakhtiyarova, K. Z., & Vakhitova, Y. V. (2019) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2019119081160 · Cited by 15
Бакаева, З. В., Surin, A. M., Lizunova, N. V., Zgodova, A., Krasilnikova, I. A., Fisenko, А. P., Frolov, D., Андреева, Л. А., Myasoedov, N. F., & Pinelis, V. G. (2020) · Doklady Biochemistry and Biophysics · doi:10.1134/s1607672920020040 · Cited by 16
Ziolkowski, L. H., Mordukhovich, I., Chen, D. M., Chisari, M., Shu, H.-J., Lambert, P. M., Qian, M., Zorumski, C. F., Covey, D. F., & Mennerick, S. J. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108358 · Cited by 15
“, 2014; Zanos and Gould, 2018) and neuroprotection (Hardingham and Bading, 2010).”
BackgroundPituitary Adenylate Cyclase-Activating Polypeptide: A Potent Therapeutic Agent in Oxidative Stress
Sadanandan, N., Cozene, B., Park, Y. J., Farooq, J., Kingsbury, C., Wang, Z.-J., Moscatello, A., Saft, M., Cho, J., Gonzales‐Portillo, B., et al. (2021) · Antioxidants · doi:10.3390/antiox10030354 · Cited by 16
“NMDA receptors that contain GluN2B subunits induce apoptosis and reduce CREB pathways via intracellular signaling pathways and caspase 3 activity [58,59].”
BackgroundLiu, H., Chen, B., Guo, B., Deng, X., Wang, B., & Dou, X. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02402-0 · Cited by 15
“formation, synaptic plasticity, neuronal survival, learning, and memory [20].”
BackgroundNMDA receptor activity determines neuronal fate: location or number?
Zhou, X., Chen, Z., Yun, W., & Wang, H. (2014) · Reviews in the Neurosciences · doi:10.1515/revneuro-2014-0053 · Cited by 15
“Actually, the term often refers to two populations, perisynaptic and extrasynaptic NMDARs (Hardingham and Bading, 2010).”
BackgroundInfluentialSung, C., Wen, Z., Feng, C., Chen, C., Huang, S., Chen, N., Chen, W.-F., & Wong, C. (2017) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12705 · Cited by 15
Gonçalves‐Pimentel, C., Moreno, G. M. M., Trindade, B. S., Isaac, A. R., Rodrigues, C. G., Savariradjane, M., de Albuquerque, A. V., Aguiar, J. L. D. A., & Andrade‐da‐Costa, B. L. D. S. (2018) · Journal of Materials Science Materials in Medicine · doi:10.1007/s10856-018-6147-0 · Cited by 15
Loss, C. M., Rosa, N. S., Mestriner, R. G., Xavier, L. L., & de Oliveira, D. L. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.01.002 · Cited by 15
“The current most accepted theory of NMDAR-mediated neurodegeneration postulates that over-activation of extrasynaptic NMDAR counteracts synaptic NMDAR and triggers cell death (Hardingham and Bading, 2010; Hardingham et al., 2002).”
BackgroundInfluentialCrevier‐Sorbo, G., Rymar, V. V., Crevier-Sorbo, R., & Sadikot, A. F. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-0878-0 · Cited by 15
Pridopidine in the treatment of Huntington’s disease
Jabłońska, M., Grzelakowska, K., Wiśniewski, B., Mazur, E., Leis, K., & Gałązka, P. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0085 · Cited by 14
Targeting the dysfunction of glutamate receptors for the development of novel antidepressants
Xia, C., He, J., Du, L., Yan, Y., Lian, W., Xu, J., & Zhang, W. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107875 · Cited by 15
Perić, I., Stanisavljević, A., Gass, P., & Filipović, D. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.05.021 · Cited by 17
Choi, I., Lee, P., Wang, W. T., Hui, D., Wang, X., Brooks, W. M., & Michaelis, E. K. (2014) · Neurochemical Research · doi:10.1007/s11064-014-1239-9 · Cited by 15
“Neurodegeneration induced by high levels of extrasynaptic Glu is associated with changes in synaptic and dendritic morphology and in the levels of many synapse-associated proteins, MAP2 being simply one such dendrite and synapse-related protein [26, 27].”
BackgroundChen, M., Jin, J., Bi, H., Zhang, Y., Sun, M., Li, X., & Wang, Y. (2025) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2025.104502 · Cited by 14
Neuroprotective role of GLT-1/EAAT2 in glutamate-induced excitotoxicity
Zhang, Y., Liu, W., Huang, T., Liu, L., & Chen, X. (2025) · Behavioural Brain Research · doi:10.1016/j.bbr.2025.115804 · Cited by 15
Back, M. K., Ruggieri, S., Jacobi, E., & von Engelhardt, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126298 · Cited by 15
“cell d ath [43,49,50], but see [51–54], we recorded synaptic and extrasynapt c NMDAR-”
BackgroundFearey, B. C., Binkle-Ladisch, L., Mensching, D., Schulze, C., Lohr, C., Friese, M. A., Oertner, T. G., & Gee, C. E. (2022) · Scientific Reports · doi:10.1038/s41598-022-09875-6 · Cited by 14
Serine Racemase Expression Differentiates Aging from Alzheimer’s Brain
Wu, S., Zhou, J., Zhang, H., & Barger, S. W. (2022) · Current Alzheimer Research · doi:10.2174/1567205019666220805105106 · Cited by 14
Isoliquiritigenin Protects Neuronal Cells against Glutamate Excitotoxicity
Zgodova, A., Павлова, С. И., Nekrasova, A., Boyarkin, D., Pinelis, V. G., Surin, A. M., & Валериевна, Б. З. (2022) · Membranes · doi:10.3390/membranes12111052 · Cited by 14
“The intracellular changes that arise during this process include the activation of Ca2+-dependent enzymes, for example, proteases, with subsequent changes in the structure and activity of many proteins both in the cytosol and the organelles [11,16].”
BackgroundFeng, H., Zhang, Z., Lyu, W., Kong, X., Li, J., Zhou, H., & Wei, P. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03864-0 · Cited by 14
“The activation of the extrasynaptic NMDAR causes loss of mitochondrial membrane potential and induces Ca 2+ neurotoxicity, ultimately resulting in LTD, spinal atrophy, synaptic loss, and apoptosis [93, 95].”
BackgroundLlorente, I. L., Landucci, E., Pellegrini-Giampietro, D. E., & Fernández‐López, A. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.02.040 · Cited by 15
“The extrasynaptic GluN1/GluN2B receptors are coupled to signaling pathways that lead to neuronal death and their blocking prevents neuron loss following stroke (Hardingham et al., 2002; Hardingham and Bading, 2010; Gladding and Raymond, 2011).”
BackgroundOsborne, D. M., Fitzgerald, D. P., O’Leary, K. E., Anderson, B. M., Lee, C. C., Tessier, P. M., & McNay, E. C. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.03.005 · Cited by 15
“AMPAR and NMDARs are important for synaptic transmission and essential for learning-associated processes including synaptogenesis and CREB activation; these actions are dependent upon the receptors being adequately trafficked to the plasma membrane (73-75).”
Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists
Leiva, R., Phillips, M. B., Turcu, A. L., Gratacòs‐Batlle, E., León-García, L., Sureda, F. X., Soto, D., Johnson, J. W., & Vázquez, S. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00154 · Cited by 14
“neurotoxic.(35-37) It is clear, however, that overactivation of synaptic NMDARs also can be neurotoxic.”
Rapid homeostatic downregulation of LTP by extrasynaptic GluN2B receptors
Delgado, J. Y., Fink, A. E., Grant, S. G. N., O’Dell, T. J., & Opazo, P. (2018) · Journal of Neurophysiology · doi:10.1152/jn.00421.2018 · Cited by 15
Amyloid-β Oligomers Regulate ADAM10 Synaptic Localization Through Aberrant Plasticity Phenomena
Marcello, E. E., Musardo, S., Vandermeulen, L., Pelucchi, S., Gardoni, F., Santo, N., Antonucci, F., & Luca, M. D. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1583-5 · Cited by 14
Targeting Synaptic NMDA Receptor Co-agonism as a Therapy for Alzheimer’s Disease?
Hardingham, G. E. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.02.009 · Cited by 14
Self-citationContribution of NAADP to Glutamate-Evoked Changes in Ca2+ Homeostasis in Mouse Hippocampal Neurons
Hermann, J., Bender, M., Schumacher, D., Woo, M. S., Shaposhnykov, A., Rosenkranz, S. C., Kuryshev, V., Meier, C., Guse, A. H., Friese, M. A., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00496 · Cited by 14
The Role of Glutamate in the Pathogenesis of Multiple Sclerosis
Kuzmina, U. S., Зайнуллина, Л. Ф., Вахитов, В. А., Bakhtiyarova, K. Z., & Vakhitova, Y. V. (2020) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-020-00953-8 · Cited by 14
“Важно отметить, что сочетание субъединиц определяет биохимические и фармакологические свойства NMDAR [47, 48].”
Viejo, L., Rubio‐Alarcón, M., Arribas, R. L., Moreno-Castro, M., Pérez-Marín, R., Braun-Cornejo, M., Estrada, M., & Rı́os, C. D. L. (2021) · Molecules · doi:10.3390/molecules26154473 · Cited by 14
“On the other hand, NMDAR is one the principal pathways of Ca2+ overload reported in neurodegenerative diseases [39].”
BackgroundPeng, W., Shen, Y., Wang, Q., Ding, J., & Wang, X. (2021) · Brain Sciences · doi:10.3390/brainsci11111465 · Cited by 14
“The NR1/ERK1/2/CREB pathway is important for dendritic spine development and function maintenance [20,21].”
BackgroundGrochowska, K. M., Bär, J., Gomes, G. M., Kreutz, M. R., & Karpova, A. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.787494 · Cited by 14
Bauersachs, H. G., Bengtson, C. P., Weiss, U. K., Hellwig, A., Vilela, C. G., Zaremba, B., Kaessmann, H., Pruunsild, P., & Bading, H. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.12.026 · Cited by 16
Self-citationWalch, E., Bilas, A., Bebawy, V., Lam, A., Murphy, T. R., Sriram, S., & Fiacco, T. A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.930384 · Cited by 14
“, 2013), extrasynaptic iGluRs, which are predominantly NMDARs, may be scattered on other parts of the neuron (Benke et al., 1993; Hardingham and Bading, 2010) and do not have privileged access to presynaptic glutamate (Köhr, 2006).”
BackgroundChen, Z., Zhou, Q., Zhang, M., Wang, H., Yun, W., & Zhou, X. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.08.003 · Cited by 14
Activity‐dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones
Wild, A. R., Jones, S., & Gibb, A. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.267310 · Cited by 13
“Elevated intracellular [Ca2+] can activate signalling pathways coupled to cell death (Hardingham & Bading, 2010; Surmeier et al. 2010), has a detrimental effect on mitochondrial function (Duchen et al. 2008) and enhances the toxic effects of a high cytosolic dopamine concentration (Mosharov et al.…”
BackgroundMethodInfluentialNmda Receptor Antagonists for Depression: Critical Considerations
Serafini, G., Gonda, X., Rihmer, Z., Pompili, M., Girardi, P., Nasrallah, H. A., & Amore, M. (2015) · Annals of Clinical Psychiatry · doi:10.1177/104012371502700308 · Cited by 15
“24 Glutamatergic abnormalities may result from the imbalance between synaptic and extrasynaptic NMDAR activity.”
Inta, I. M., Vogt, M. A., Vogel, A. S., Bettendorf, M., Gass, P., & Inta, D. (2015) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-015-0649-2 · Cited by 14
“The contrasting effects on cell death mediated via NMDAR were shown to depend on the activation of different intracellular signaling cascades [23].”
BackgroundArmstead, W. M., Riley, J., Yarovoi, S. V., Higazi, A. A., & Cines, D. B. (2016) · Stroke · doi:10.1161/strokeaha.116.012678 · Cited by 14
“sustained levels of activation of extrasynaptic NMDA-Rs may promote cell death.(33,34) This, in turn, may depend on the expres-”
BackgroundThe regulatory effect of electro-acupuncture on the expression of NMDA receptors in a SCI rat model
Tu, W., Chen, W., Xia, W., He, R., Hu, J., Jiang, M. C., & Jiang, S.-H. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.04.004 · Cited by 14
Lautz, J. D., Gniffke, E. P., Brown, E., Immendorf, K. B., Mendel, R. D., & Smith, S. E. P. (2019) · Scientific Reports · doi:10.1038/s41598-019-46690-y · Cited by 12
Karanikas, E. (2025) · Psychopharmacology Bulletin · doi:10.64719/pb.4419 · Cited by 14
Ahmed, H., Zheng, M., Smart, K. A., Fang, H., Zhang, L., Emery, P. R., Gao, H., Ropchan, J. R., Haider, A., Tamagnan, G. D., et al. (2022) · Journal of Nuclear Medicine · doi:10.2967/jnumed.122.263977 · Cited by 13
“The GluN1/2B receptors are associated with several neuropatholo-gies, such as Alzheimer ’ s disease, Parkinson ’ s disease, depression, schizophrenia, and stroke, among others ( 2 – 5 ).”
BackgroundLiu, Y., Zhao, H., Li, Q., Cui, H.-W., & Huang, G. (2022) · Aging and Disease · doi:10.14336/ad.2022.1211 · Cited by 15
“GluN2A and GluN2B can be detected in both synaptic and extrasynaptic NMDARs in the adult brain, with GluN2A mainly located in synaptic NMDARs and GluN2B mainly in extrasynaptic NMDARs [38].”
BackgroundDrugs with glutamate-based mechanisms of action in psychiatry
Chrobak, A., & Siwek, M. (2024) · Pharmacological Reports · doi:10.1007/s43440-024-00656-8 · Cited by 11
“However, in pathological circumstances, excessive influxes of Ca 2+ in neuronal deterioration or death [17].”
Terry-Lorenzo, R. T., Fan, R. H., Khin, N. A., & Singh, J. B. (2024) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae066 · Cited by 14
Shangguan, T., Xu, J., Weng, X., & Lin, H. T. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1504123 · Cited by 14
“This dysregulation enables glutamate to bind to extra synaptic N-methyl-D-aspartate (NMDA) receptors, thereby inhibiting growth factors and induces excitotoxicity, and contributing to the development of depression (63).”
Kimura, J., Nemoto, K., Degawa, M., Yokosuka, A., Mimaki, Y., Shimizu, K., Oku, N., & Ohizumi, Y. (2014) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b14-00177 · Cited by 13
Novel rapid-acting antidepressants: molecular and cellular signaling mechanisms
Thomas, A. M., & Duman, R. S. (2017) · Neuronal Signaling · doi:10.1042/ns20170010 · Cited by 14
“In addition to activating in response to different patterns of glutamate release, GluN2B subunits transmit a different set of intracellular signals than GluN2A subunits and may be most prevalent at a different part of the postsynaptic neurone [37].”
Parrish, R. R., Codadu, N. K., Racca, C., & Trevelyan, A. J. (2018) · Journal of Neurophysiology · doi:10.1152/jn.00287.2018 · Cited by 13
Jacobi, A. A., Halawani, S. M., Lynch, D. R., & Lin, H. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.10.055 · Cited by 12
Leyrer‐Jackson, J. M., Olive, M. F., & Gipson, C. D. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9077-1_9 · Cited by 14
Young, D. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00635 · Cited by 13
GluA3 autoantibodies induce alterations in dendritic spine and behavior in mice
Scheggia, D., Stanic, J., Italia, M., Greca, F. L., Zianni, E., Benussi, A., Borroni, B., Luca, M. D., & Gardoni, F. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.07.001 · Cited by 13
“2E,F) were not altered by the treatment with anti-GluA3 IgG thus suggesting no alteration of the main signaling pathways associated to the activation of synaptic glutamate receptors (Hardingham and Bading, 2010).”
Dong, H., Yang, X., & Sun, Z. (2021) · Cognitive Neurodynamics · doi:10.1007/s11571-021-09705-x · Cited by 13
Alfaro‐Ruiz, R., Aguado, C., Martín‐Belmonte, A., Moreno‐Martínez, A. E., Merchán‐Rubira, J., Hernández, F., Ávila, J., Fukazawa, Y., & Luján, R. (2022) · Brain Pathology · doi:10.1111/bpa.13115 · Cited by 14
“NMDARs are not only found at synaptic sites but also at extrasynaptic locations [21].”
BackgroundInfluentialBansal, Y., Fee, C., Misquitta, K. A., Codeluppi-Arrowsmith, S. A., Sibille, E. L., Berman, R., Coric, V., Sanacora, G., & Banasr, M. (2023) · Complex Psychiatry · doi:10.1159/000529534 · Cited by 12
Yamagata, Y., Kaneko, K., Kase, D., Ishihara, H., Nairn, A. C., Obata, K., & Imoto, K. (2013) · Brain Research · doi:10.1016/j.brainres.2013.02.015 · Cited by 13
“…plasticity, and learning and memory through phosphorylation of various substrates, such as transcription factors, cytoskeletal proteins, regulatory enzymes and kinases in postmitotic neurons (Hardingham and Bading, 2010; Subramaniam and Unsicker, 2006; Sweatt, 2004; Thomas and Huganir, 2004).”
BackgroundYamamoto, T., Mencarelli, M. A., Marco, C. D., Mucciolo, M., Vascotto, M., Balestri, P., Gérard, M., Mathieu‐Dramard, M., Andrieux, J., Breuning, M. H., et al. (2014) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2014.02.001 · Cited by 13
Sun, Y., Chen, Y., Zhan, L., Zhang, L., Hu, J. H., & Gao, Z. (2015) · Reviews in the Neurosciences · doi:10.1515/revneuro-2015-0037 · Cited by 13
“It is generally accepted that synaptic and extrasynaptic NMDARs have opposite effects on neuronal survival and death (Hardingham and Bading, 2010).”
BackgroundTian, M., Xu, J., Lei, G., Lombroso, P. J., Jackson, M. F., & MacDonald, J. F. (2016) · Scientific Reports · doi:10.1038/srep36684 · Cited by 13
Ambroziak, W., Fourie, C., & Montgomery, J. M. (2018) · Hippocampus · doi:10.1002/hipo.22995 · Cited by 13
Okamoto, S., Prikhodko, O., Piña-Crespo, J., Adame, A., McKercher, S. R., Brill, L. M., Nakanishi, N., Oh, C.-K., Nakamura, T., Masliah, E., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.03.029 · Cited by 13
“Moreover, activation of eNMDARs is known to be associated with synaptic pathology, whereas their inhibition by drugs like the aminoadamantanes can protect from synapse loss (Hardingham and Bading, 2010; Okamoto et al., 2009; Parsons and Raymond, 2014; Takahashi et al., 2015; Talantova et al., 2013).”
BackgroundSalek, A. B., Edler, M., McBride, J. P., & Baucum, A. J. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14831 · Cited by 13
Manisha, C., Ayyamperumal, S., Selvaraj, J., Nanjan, C. M. J., Joghee, N. M., Clement, J. P., & Justin, A. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.109794 · Cited by 13
Dong, L.-D., Chen, J., Li, F., Gao, F., Wu, J., Miao, Y., & Wang, Z. (2013) · Neural Plasticity · doi:10.1155/2013/670254 · Cited by 13
Polyamines as Snake Toxins and Their Probable Pharmacological Functions in Envenomation
Aird, S. D., Villar‐Briones, A., Roy, M. C., & Mikheyev, A. S. (2016) · Toxins · doi:10.3390/toxins8100279 · Cited by 13
“Hardingham and Bading [101] report that neuronal NMDARs comprise two populations: synaptic receptors, which are neuroprotective, and extrasynaptic receptors that promote excitotoxicity and neuronal death.”
BackgroundKosheleva, L., Koshelev, D., Lagunas‐Rangel, F. A., Levit, S., Rabinovitch, A., & Schiöth, H. B. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100044 · Cited by 12
“Glutamate N-Methyl-D-Aspartate receptors (NMDARs) activate by binding both glycine and glutamate, with the concomitant depolarization of the cell membrane (Hardingham and Bading, 2010).”
Calpain-1 and Calpain-2 in the Brain: What Have We Learned from 45 Years of Research?
Baudry, M., & Bi, X. (2025) · Cells · doi:10.3390/cells14171301 · Cited by 12
“Activation of synaptic NMDA receptors has been shown to be neuroprotective by stimulating the Akt survival pathway, while activation of extrasynaptic NMDA receptors is linked to a neurodegenerative pathway [108,109].”
Pharmacology of ketamine and esketamine as rapid-acting antidepressants
Pavlidi, P., Megalokonomou, A., Sofron, A., Kokras, N., & Dalla, C. (2021) · Psychiatriki · doi:10.22365/jpsych.2021.050 · Cited by 12
León, B. E., Peyton, L., Essa, H., Wieden, T., Marion, N., Childers, W. E., Abou-Gharbia, M. A., & Choi, D. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109515 · Cited by 12
Jos, S., Poulose, R., Kambaru, A., Gogoi, H., Nanjaiah, N. D., Padmanabhan, B., Mehta, B., & Padavattan, S. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168445 · Cited by 12
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
