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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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The Rac1 Inhibitor NSC23766 Suppresses CREB Signaling by Targeting NMDA Receptor Function
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Niciu, M. J., Henter, I. D., Sanacora, G., & Zarate, C. A. (2013) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2013.829585 · Cited by 36
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“Our data indicate that the eNMDAR, a key player in neurodegenerative processes (25-28), is responsible for excitotoxicity-associated nuclear accumulation”
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Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets
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“…GluN2 subunits: in the adult brain GluN2A-containing NMDARs are present mainly at synapses, whereas GluN2Bs are located predominantly extrasynaptically, a difference with important consequences, leading, for example, to distinct, even opposite roles in cell survival (Hardingham and Bading, 2010).”
The Adenosine Neuromodulation System in Schizophrenia
Rial, D., Lara, D. R., & Cunha, R. A. (2014) · International review of neurobiology · doi:10.1016/b978-0-12-801022-8.00016-7 · Cited by 35
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“264 1989) clearly suggests that it has a direct involvement in neuronal communication via calcium mediating signaling (Hardingham and Bading 2010).”
BackgroundNanostructured Antagonist of Extrasynaptic NMDA Receptors
Savchenko, A., Braun, G. B., & Molokanova, E. (2016) · Nano Letters · doi:10.1021/acs.nanolett.6b01988 · Cited by 32
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“NMDA receptors and AMPA receptors have been shown to be essential for synaptic plasticity, which is considered as the basis for spatial learning andmemory formation (Hardingham and Bading, 2010; Zhang et al., 2013; Zhou et al., 2018).”
BackgroundNMDA receptor modulation of glutamate release in activated neutrophils
del Arroyo, A. G., Hadjihambi, A., Sanchez, J., Turovsky, E. A., Kasymov, V., Cain, D. J., Nightingale, T. D., Lambden, S., Grant, S. G. N., Gourine, A. V., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.004 · Cited by 31
“In contrast to NMDAR-mediated neuronal injury triggered by sustained elevations in extracellular glutamate, activation of neuroprotective signalling cascades requires tonic, transient exposure of NMDAR to lower extracellular glutamate concentrations [41,42].”
BackgroundAraminia, B., Shalbafan, M., Mortezaei, A., Shirazi, E., Ghaffari, S., Sahebolzamani, E., Mortazavi, S. H., Shariati, B., Ardebili, M. E., Aqamolaei, A., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.02.020 · Cited by 32
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“In contrast, synaptic NMDARs stimulate CREB phosphorylation [6], which, in turn, initiates synaptogenesis in the hippocampus and NAc [47,48].”
BackgroundInfluentialHuman torpor: translating insights from nature into manned deep space expedition
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“N-methyl-D-aspartate receptors (NMDARs), a cation channel gated byGlu, are critical inmediating excitotoxicity and synaptic plasticity (Hardingham & Bading, 2010).”
BackgroundKopchock, R. J., Ravi, B., Bode, A., & Collins, K. M. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2150-20.2021 · Cited by 32
Šterk, M., Bombek, L. K., Klemen, M. S., Rupnik, M. S., Marhl, M., Stožer, A., & Gosak, M. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009002 · Cited by 31
“This is consistent with the reports showing neuronal cell death after high-glutamate-mediated excitotoxicity via excessive activation of NMDARs in the CNS [48].”
ResultZhang, X., Shi, X., Wang, J., Xu, Z., & He, J. (2021) · Aging · doi:10.18632/aging.203462 · Cited by 30
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Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes
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“Specifically, the calcium influx through extrasynaptic GluN2B-containing NMDARs blocks BDNF expression by inactivating CREB and leads to mitochondrial dysfunction and cell death (Hardingham and Bading, 2010; Hardingham et al., 2002).”
BackgroundGrochowska, K. M., Gomes, G. M., Raman, R., Kaushik, R., Sosulina, L., Kaneko, H., Oelschlegel, A. M., Yuanxiang, P., Reyes‐Resina, I., Bayraktar, G., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022112453 · Cited by 31
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Anesthetic action on extra-synaptic receptors: effects in neural population models of EEG activity
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“ical for normal brain function including synaptic plasticity and learning and memory, while extrasynaptic NMDARs may play a predominant role in pathological situations (Hardingham and Bading, 2010).”
Changes in the Adult GluN2B Associated Proteome following Adolescent Intermittent Ethanol Exposure
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“Huntington’s disease, ischemia, Parkinson’s disease, Alzheimer's disease [42, 43] and it could be this aberrant signaling that causes the prolonged effects from AIE.”
BackgroundSynaptic Conductances during Interictal Discharges in Pyramidal Neurons of Rat Entorhinal Cortex
Amakhin, D. V., Ergina, J. L., Chizhov, A. V., & Zaitsev, A. V. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00233 · Cited by 31
“The prolonged excessive activation of NMDARs with subsequent overload of Ca2+ entry is deleterious (Hardingham and Bading, 2010).”
BackgroundResultHyperhomocysteinemia leads to exacerbation of ischemic brain damage: Role of GluN2A NMDA receptors
Jindal, A., Rajagopal, S., Winter, L., Miller, J. W., Jacobsen, D. W., Brigman, J. L., Allan, A. M., Paul, S., & Poddar, R. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.03.012 · Cited by 33
“From the morphological point of view, receptors are often considered extrasynaptic if they are situated more than 100 nm away from the post-synaptic density (Hardingham and Bading, 2010; Petralia et al., 2010).”
BackgroundRapid exchange of synaptic and extrasynaptic NMDA receptors in hippocampal CA1 neurons
McQuate, A. L., & Barría, A. (2020) · Journal of Neurophysiology · doi:10.1152/jn.00458.2019 · Cited by 31
Targeting NMDA Receptors in Emotional Disorders: Their Role in Neuroprotection
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“Studies have found that activation of synaptic NMDARs can inhibit the expression of the pro-apoptotic gene Puma and nuclear translocation of the death transcription factor forkhead box O (FOXO) [52,58].”
BackgroundSynapse Dysfunctions in Multiple Sclerosis
Schwarz, K., & Schmitz, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021639 · Cited by 36
Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review
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“Extrasynaptic NMDA stimulation is related to long-term desensitization, whereas NMDA excitotoxicity and synaptic activity are essential for long-term potentiation and memory formation [18, 92, 93].”
BackgroundINTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia
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“Antagonism of NMDARs has been shown to induce schizophrenia-like psychosis and cognitive impairment in healthy individuals and worsen symptoms in schizophrenia (Domino and Luby, 2012).”
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“To investigate the possible involvement of D-serine in the neuroprotective effects of CX3CL1, excitotoxicity experiments were performed in the presence of DAAO (0.1 U/ml) and catalase (300 U/ml), to remove extracellular serine and the hydrogen peroxide by-products, respectively.”
InfluentialExtracellular Ca2+ ions reduce NMDA receptor conductance and gating
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“…and extra synaptic NMDA receptors controls the cellular effect of the Ca2+ influx such that activation of synaptic receptors generally promotes cell survival and synaptic plasticity, whereas activation of extrasynaptic receptors can initiate apoptotic cascades (Hardingham and Bading, 2010).”
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“Several lines of evidence indicate the subtype and location of activated NMDARs are key determinants of the nature of NMDAR signaling and resultant physiological and pathophysiological processes (Hardingham et al. 2002; Liu et al. 2007; Hardingham and Bading 2010).”
Schlüter, A., Aksan, B., Fioravanti, R., Valente, S., Mai, A., & Mauceri, D. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01658-x · Cited by 31
“and neuroprotection, while stimulation of extrasynaptic NMDARs (eNMDARs) causes cell death [15, 21].”
BackgroundKhacho, P., Wang, B., Ahlskog, N., Hristova, E., & Bergeron, R. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.08.017 · Cited by 30
“NAAG on extrasynaptic NMDARs in adult mice (Hardingham et al., 2002; Carpenter-Hyland et al., 2004; Harney et al., 2008; Imamura et al., 2008; Okamoto et al., 2009; Hardingham and Bading, 2010; Xia et al., 2010; Li et al., 2011).”
InfluentialProsurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus
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“…et al., 2005, Yin et al., 2005, Xu et al., 2007), along with others in the field (Soriano et al., 2006, Lin et al., 2008) (Hardingham et al., 2002; Hardingham and Bading, 2010), suggest that intensity of NMDA receptor activation and type of NMDA receptor subtype activated determines whether a…”
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“Despite remarkable antiexcitotoxic properties, this class of compounds largely failed in clinical trials because of adverse psychotomimetic events (1,6).”
BackgroundYao, Y., Ju, P., Liu, H., Wu, X., Niu, Z., Zhu, Y., Zhang, C., & Fang, Y. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05469-0 · Cited by 33
Extrasynaptic NMDA Receptors Bidirectionally Modulate Intrinsic Excitability of Inhibitory Neurons
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“Intracellular Ca2+ overload results in inappropriate activation of distinct signaling pathways and enzymes (such as calpains and other calcium-regulated enzymes) that lead to neuronal death (Berliocchi et al., 2005; Coyle and Puttfarcken, 1993; Hardingham and Bading, 2010).”
BackgroundXiao, Z., Jaiswal, M. K., Deng, P., Matsui, T., Shin, H., Porter, J. E., & Lei, S. (2011) · Hippocampus · doi:10.1002/hipo.20984 · Cited by 30
“functions (Gladding and Raymond, 2011; Hardingham and Bading, 2010).”
Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?
Senatore, A., Restelli, E., & Chiesa, R. (2013) · International Journal of Cell Biology · doi:10.1155/2013/543803 · Cited by 29
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“In addition to NMDAR subunit composition, the location of membranebound GluN2A- and GluN2B-containing NMDARs (i.e., synaptic vs. extrasynaptic compartments) can also influence learning-dependent synaptic plasticity (Hardingham and Bading, 2010).”
BackgroundChandrasekar, A., Aksan, B., Heuvel, F. O., Förstner, P., Sinske, D., Rehman, R., Palmer, A., Ludolph, A., Huber-Lang, M., Böckers, T., et al. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2017.12.017 · Cited by 29
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“The stable or even progressive NR2B phosphorylation reported here might suggest an upstream role of NMDA in the seizure-related plasticity, possibly through the activation of downstream signaling pathways leading to cell changes in the postsynaptic neurons [75–76] or cell death particularly if extrasynaptic NMDA recep…”
BackgroundNaskar, K., & Stern, J. E. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.270793 · Cited by 28
“The fact that this effect persisted when synaptic NMDARs were blocked (i.e. 4-AP/MK801 protocol) (Hardingham et al. 2002; Jung et al. 2008; Hardingham & Bading, 2010), but was blunted when eNMDARs were rendered inactive by removing the eNMDAR (but not sNMDAR) co-agonist glycine (Papouin et al.…”
BackgroundRafe, M. R., Saha, P., & Bello, S. T. (2024) · Behavioural Brain Research · doi:10.1016/j.bbr.2024.115173 · Cited by 29
Wang, H., Morishita, Y., Miura, D., Naranjo, J. R., Kida, S., & Zhuo, M. (2012) · Molecular Brain · doi:10.1186/1756-6606-5-27 · Cited by 30
“CREB is a transcriptional factor that plays important roles in synaptic plasticity [40-45,52].”
BackgroundChen, Y.-W., Actor-Engel, H. S., Sherpa, A. D., Klingensmith, L., Chowdhury, T. G., & Aoki, C. J. (2016) · Brain Structure and Function · doi:10.1007/s00429-016-1341-7 · Cited by 27
“Unlike the excitotoxic and apoptotic roles ascribed to extra-synaptic NR2B-NMDARs expressed by cultured neurons (Hardingham and Bading 2010; Kaufman et al. 2012), the consequence of elevating extra-synaptic spine membrane NMDAR in vivo by exercise during adolescence may be to prune synapses,…”
BackgroundMethodPridopidine: Overview of Pharmacology and Rationale for its Use in Huntington’s Disease
Waters, N., Tedroff, J., Pontén, H., Klamer, D., Sonesson, C., & Waters, N. (2018) · Journal of Huntington s Disease · doi:10.3233/jhd-170267 · Cited by 30
“Memantine has been shown to display neuroprotective effects in vivo [118, 119].”
BackgroundZhan, J., Zheng, L., Chen, H., Yu, B., Wang, W., Wang, T., Ruan, B., Pan, B.-X., Chen, J.-R., Li, X.-F., et al. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00390 · Cited by 27
“GluN2B-containing NMDARs are proposed to mainly localize on the extrasynaptic site and considered as a crucial factor involved in apoptosis (Hardingham and Bading, 2010; Zhou et al., 2015).”
BackgroundJelen, L. A., King, S., Horne, C. M., Lythgoe, D. J., Young, A. H., & Stone, J. M. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2018.12.005 · Cited by 29
“This glutamate excess can activate extrasynaptic NMDARs, resulting in atrophy of dendritic spines, loss of synaptic integrity and neuronal loss (Hardingham and Bading, 2010).”
BackgroundSpatial Coupling Tunes NMDA Receptor Responses via Ca2+Diffusion
Iacobucci, G. J., & Popescu, G. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0901-19.2019 · Cited by 29
Neuroimmune Mechanisms and Sex/Gender-Dependent Effects in the Pathophysiology of Mental Disorders
Kokkosis, A. G., & Tsirka, S. E. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.120.266163 · Cited by 29
“stimulate extrasynaptic neuronal NMDARs and lead to BDNF loss and excitotoxicity (Hardingham et al., 2002; Hardingham and Bading, 2010).”
BackgroundChen, X., Beltran, D. J., Tsygankova, V., Woolwine, B. J., Patel, T., Baer, W. M., Felger, J. C., Miller, A. H., & Haroon, E. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01587-1 · Cited by 31
Lane, H., Wang, S., & Lin, C. (2022) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13504 · Cited by 28
“Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.”
BackgroundInfluentialStriatal-Enriched Protein Tyrosine Phosphatase in Alzheimer’s Disease
Xu, J., Kurup, P. K., Nairn, A. C., & Lombroso, P. J. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00009-x · Cited by 29
“These receptors are localized in distinct compartments on the neuronal membrane where they initiate signaling pathways when activated by glutamate (Hardingham & Bading, 2010; Ivanov et al., 2006).”
BackgroundLi, Y., Sun, W., Han, S., Li, J., Ding, S., Wang, W., & Yin, Y. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9647-7 · Cited by 31
“Although there is a controversy on the function of synaptic and extrasynaptic NMDARs in neuronal pro-survival or pro-death [24], recent studies indicate synaptic NMDARs contribute to either NMDA-induced neurotoxicity or hypoxic excitotoxic death [25, 26].”
Glutamatergic mechanisms in l-DOPA-induced dyskinesia and therapeutic implications
Mellone, M., & Gardoni, F. (2018) · Journal of Neural Transmission · doi:10.1007/s00702-018-1846-8 · Cited by 29
“NMDAR activity and intracellular signaling (Hardingham and Bading 2010; Parsons and Raymond 2014).”
BackgroundHuang, G., Liu, Y., Zhu, X., He, L., & Chen, T. (2025) · Exploration · doi:10.1002/exp.20240415 · Cited by 28
“Therefore, achieving a balanced regulation of synaptic and extra-synaptic NMDARs presented potential therapeutic value for AD [119, 120].”
Hou, J., Klippel, K., & Bose, P. (2025) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl38904 · Cited by 29
“For instance, sustained activation of NMDA receptors can trigger signaling pathways that internalize receptors or favor sub-unit configurations with lower calcium permeability [63].”
Yu, W., Bonnet, M., Farso, M. C., Ma, K., Chabot, J., Martin, E., Torriglia, A., Guan, Z.-Z., McLaurin, J., Quirion, R., et al. (2014) · BMC Neuroscience · doi:10.1186/1471-2202-15-73 · Cited by 29
“Moreover, cyclin D1 induction has been involved in neuronal death, as shown in hippocampal [45,46] and cortical [47,48] neurons, in vitro, as well as animal and human AD post-mortem tissues [49,50].”
BackgroundChe, A., Truong, D. T., FITCH, R. H., & LoTurco, J. J. (2015) · Cerebral Cortex · doi:10.1093/cercor/bhv168 · Cited by 27
“Similarly, evidence has accumulated that NMDARs at locations other than the PSD may play important roles in neuropathologies (Lipton 2006; Zhao 2006; Okamoto et al. 2009; Hardingham and Bading 2010; Talantova et al. 2013), which were previously attributed to postsynaptic NMDARs.”
BackgroundSperber, P. S., Siegerink, B., Huo, S., Rohmann, J. L., Piper, S. K., Prüß, H., Heuschmann, P. U., Endres, M., & Liman, T. (2019) · Stroke · doi:10.1161/strokeaha.119.026100 · Cited by 28
“However, the role of NMDARs in stroke remains controversial, depending on their location, and the duration of activation.(4,5) Anti-NMDA-receptor GluN1 (also NR1) antibodies (NMDAR1-abs) of the immunoglobulin (Ig-) isotypes A and M have been repeatedly found in blood serum samples of healthy elderly individuals, indic…”
BackgroundLi, W., Marta Kutas, A., Gray, J. A., Hagerman, R. J., & Olichney, J. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.09.023 · Cited by 27
“BDNF has been implicated in rescuing neurons from NMDAR blockade-induced neuronal death and in regulating all phases (induction, maintenance, and synaptic consolidation) of LTP (Panja and Bramham, 2014).”
BackgroundInfluentialChen, S., Hsieh, C.-P., Lee, M.-Y., Chen, L.-C., Huang, C.-M., Chen, H., & Chan, M. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112369 · Cited by 28
Inhibition of CK2 mitigates Alzheimer’s tau pathology by preventing NR2B synaptic mislocalization
Marshall, C. A., McBride, J. D., Changolkar, L. N., Riddle, D. M., Trojanowski, J. Q., & Lee, V. M. ‐. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01331-w · Cited by 28
“that an increase in extrasynaptic NR2B function may arise in AD patients due to an increase in extrasynaptic receptors, which could facilitate an increase in neurotransmission from glutamate spillover [15, 19, 33, 46, 63].”
BackgroundIn the fast lane: Receptor trafficking during status epilepticus
Naylor, D. E. (2023) · Epilepsia Open · doi:10.1002/epi4.12718 · Cited by 27
Chang, C.-Z., Wu, S., Kwan, A., & Lin, C. (2015) · World Neurosurgery · doi:10.1016/j.wneu.2015.08.071 · Cited by 28
RetractedBeta cell glutamate receptor antagonists: novel oral antidiabetic drugs?
Wollheim, C. B., & Maechler, P. (2015) · Nature Medicine · doi:10.1038/nm.3835 · Cited by 28
Downregulation of Src-Kinase and Glutamate-Receptor Phosphorylation after Traumatic Brain Injury
Park, Y., Luo, T., Zhang, F., Liu, C., Bramlett, H. M., Dietrich, W. D., & Hu, B. R. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.121 · Cited by 29
Rajput, P. S., Kharmate, G., Norman, M. A., Liu, S., Sastry, B. R., Brunicardi, C. F., & Kumar, U. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024467 · Cited by 28
“Furthermore, recent studies have shown the distinct role of synaptic and extrasynaptic NMDARs in early and late onset of HD [56,57,58].”
ResultRussi, M. A., Vandresen-Filho, S., Rieger, D. K., Costa, A. P., Lopes, M. W., da Cunha, R. M. S., Teixeira, E. H., Nascimento, K. S., Cavada, B. S., Tasca, C. I., et al. (2011) · Neurochemical Research · doi:10.1007/s11064-011-0608-x · Cited by 28
Serine racemase: a key player in apoptosis and necrosis
Canu, N., Ciotti, M. T., & Pollegioni, L. (2014) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2014.00009 · Cited by 29
Lan, Y., Zou, S., Chen, J.-J., Zhao, J., & Li, S. (2016) · Neural Plasticity · doi:10.1155/2016/4626593 · Cited by 29
“The association of AQP4 and GLT-1 could greatly supplement previous research regarding neuroprotection against AD.”
ResultYang, X., Tang, Y., Qiu, Q., Wu, W., Zhang, F.-L., Liu, Y., & Huang, W. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b03826 · Cited by 33
Nuzzo, T., Miroballo, M., Casamassa, A., Mancini, A., Gaetani, L., Nisticò, R., Eusebi, P., Katane, M., Homma, H., Calabresi, P., et al. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140537 · Cited by 30
Turcu, A. L., Companys-Alemany, J., Phillips, M. B., Patel, D. S., Griñán-Ferré, C., Loza, M. I., Brea, J. M., Pérez, B., Soto, D., Sureda, F. X., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114354 · Cited by 27
Dong, B., Yang, Y., Han, D., & Wang, Y. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1174738 · Cited by 30
“This reduction induced a decrease in the transmission of GluN2B-dependent signaling molecules that contribute to long-term potentiation and synaptic plasticity (Hardingham and Bading, 2010; Lussier et al., 2015), followed by decreased NMDAR function and NMDAR-related cognitive decline (Clayton and Browning, 2001; Magn…”
BackgroundShang, Y., Zhang, J., & Huang, E. J. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3577-17.2018 · Cited by 27
“In contrast, activation of GluN2A at the synapse provides a prosurvival mechanism by activating the ERK-CREB signaling pathway to promote the expression of prosurvival genes (Hardingham and Bading, 2010).”
BackgroundZhao, P., Yang, J., Wang, Y., Hao, Y., Li, Y., Li, N., Wang, J., Niu, Y., Sun, T., & Yu, J. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2572-1 · Cited by 27
Expansion microscopy: enabling single cell analysis in intact biological systems
Alon, S., Huynh, G. H., & Boyden, E. S. (2018) · FEBS Journal · doi:10.1111/febs.14597 · Cited by 27
“While stimulation of NMDARs located at synaptic clefts can promote neuronal survival, stimulation of NMDARs just 100 nm away can contribute to neuronal death [10].”
BackgroundAhmed, H., Haider, A., Varisco, J., Stanković, M., Wallimann, R. H., Gruber, S., Iten, I., Häne, S., Herde, A. M., Keller, C., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00812 · Cited by 27
Levi, L. A., Inbar, K., Nachshon, N., Bernat, N., Gatterer, A., Inbar, D., & Kupchik, Y. M. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0929-19.2019 · Cited by 26
“This should be reflected as slower current decays and may indicate an increase in the proportion of extrasynaptic NMDA receptors, as GluN2B-expressing NMDA receptors tend to localize outside of the synapse (Hardingham and Bading, 2010; Gladding and Raymond, 2011; Paoletti et al., 2013; Naassila and Pierrefiche, 2019).”
BackgroundNMDA receptor-mediated CaMKII/ERK activation contributes to renal fibrosis
Zhou, J., Liu, S., Guo, L., Wang, R., Chen, J., & Shen, J. Y. (2020) · BMC Nephrology · doi:10.1186/s12882-020-02050-x · Cited by 26
“All subunits have a conserved domain organization, including an extracellular amino-terminal domain, an extracellular ligand–binding domain, a transmembrane domain, and an intracellular carboxy–terminal domain [20, 21].”
BackgroundRecent Insights on Glutamatergic Dysfunction in Alzheimer’s Disease and Therapeutic Implications
Pinky, P. D., Pfitzer, J. C., Senfeld, J. I., Hong, H., Bhattacharya, S., Suppiramaniam, V. D., Qureshi, I., & Reed, M. N. (2022) · The Neuroscientist · doi:10.1177/10738584211069897 · Cited by 27
“A second consequence of increased extracellular glutamate levels is a spillover of glutamate outside the synaptic cleft, which can lead to overactivation of E-NMDARs and a resultant increase in both compensatory and pro-death signaling pathways (Caba and others 2021; Hardingham and Bading 2010).”
BackgroundInfluential
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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