NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders
Abstract
The number and subunit composition of synaptic N-methyl-D-aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal-lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.
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Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke.
“Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [4]
Low activity of NMDA receptors produces symptoms of schizophrenia.
“Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [4]
The persisting amnesia in patients who recover from anti-NMDA-receptor encephalitis is compatible with disruption of the mechanisms of synaptic plasticity, thought to underlie learning and memory, in which NMDA receptors play a key part.
“This feature is compatible with disruption of the mechanisms of synaptic plasticity, thought to underlie learning and memory, in which the NMDA receptors play a key part.4”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [4]
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A Molecular Mechanism for Stabilization of Learning-Induced Synaptic Modifications
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NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity
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Endocytosis and Degradative Sorting of NMDA Receptors by Conserved Membrane-Proximal Signals
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PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating
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Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras
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PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat
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Central sensitization: a generator of pain hypersensitivity by central neural plasticity
Latremoliere, A., & Woolf, C. J. (2009) · The Journal of Pain · doi:10.1016/j.jpain.2009.06.012 · Cited by 3,913 · see citing works
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., Dessain, S. K., Rosenfeld, M. R., Balice-Gordon, R., & Lynch, D. R. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70224-2 · Cited by 3,488 · see citing works
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Paoletti, P., Bellone, C., & Zhou, Q. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3504 · Cited by 2,523 · see citing works
“Lateral diffusion (1), exocytosis and endocytosis (2) and”
BackgroundSynaptic plasticity and addiction
Kauer, J. A., & Malenka, R. C. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2234 · Cited by 1,397 · see citing works
“A subunit switch between particular NMDAR subunits can also up- or downregulate NMDAR-mediated synaptic currents so that more or less Ca 2+ will enter the postsynaptic neuron during receptor activation, thereby altering the induction of synaptic plasticity”
BackgroundCellular and synaptic mechanisms of anti-NMDA receptor encephalitis
Hughes, E. G., Peng, X., Gleichman, A. J., Lai, M., Zhou, L., Tsou, R., Parsons, T. D., Lynch, D. R., Dalmau, J., & Balice-Gordon, R. J. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0167-10.2010 · Cited by 1,143 · see citing works
“Central to these neurological functions is the proper synaptic localization and trafficking of the excitatory glutamate NMDA and AMPA receptors (Lau and Zukin, 2007; Shepherd and Huganir, 2007).”
BackgroundDysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring
Stephan, K. E., Friston, K. J., & Frith, C. D. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbn176 · Cited by 1,134 · see citing works
“cell membrane as well as their endocytosis, and these mechanisms are known to be highly relevant for pathophysiological processes in several brain diseases.(30) Furthermore, the conductance properties of NMDARs depend on their phos-”
BackgroundMetaplasticity: tuning synapses and networks for plasticity
Abraham, W. C. (2008) · Nature reviews. Neuroscience · doi:10.1038/nrn2356 · Cited by 1,119 · see citing works
“It has been suggested that NMDAR activation results in LTD of NMDAR currents (LTD NMDAR ), which are crucial for the induction of conventional LTD and LTP and are known to be highly plastic in their function and localization (for reviews, see Ref”
BackgroundTrkB signalling pathways in LTP and learning
Minichiello, L. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2738 · Cited by 1,055 · see citing works
“This provides another dynamic and potentially powerful mechanism for regulating synaptic efficacy and remodellin”
BackgroundLisman, J. E., Coyle, J. T., Green, R. W., Javitt, D. C., Benes, F. M., Heckers, S., & Grace, A. A. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.02.005 · Cited by 1,010 · see citing works
“The possibilities include reduction in the concentrations of the co-agonists, glycine [38,39] and D-serine levels [40], elevated levels of endogenous antagonists (NAAG/kynurenic acid) [41,42], alterations in the redox state of the NMDA channel [43] or reduced channel expression or trafficking [13,44].”
BackgroundPape, H.-C., & Pare, D. (2010) · Physiological Reviews · doi:10.1152/physrev.00037.2009 · Cited by 994 · see citing works
Lancaster, E., Lai, M., Peng, X., Hughes, E. G., Constantinescu, R., Raizer, J. J., Friedman, D. J., Skeen, M. B., Grisold, W., Kimura, A., et al. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70324-2 · Cited by 920 · see citing works
Epigenomic Profiling Reveals DNA-Methylation Changes Associated with Major Psychosis
Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., Bouchard, L., Jia, P., Assadzadeh, A., Flanagan, J., Schumacher, A., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.01.008 · Cited by 773 · see citing works
“and proteins associated with mitochondrial function and oxidative stress responses were the most altered group.(25) Traditional etiological studies of complex disease, both genetic and epigenetic, have tended to investigate discrete regions of DNA in isolation.”
BackgroundThe neurobiology of psychedelic drugs: implications for the treatment of mood disorders
Vollenweider, F. X., & Kometer, M. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2884 · Cited by 723 · see citing works
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels
Hansen, K. B., Wollmuth, L. P., Bowie, D., Furukawa, H., Menniti, F. S., Sobolevsky, A. I., Swanson, G. T., Swanger, S. A., Greger, I. H., Nakagawa, T., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000131 · Cited by 686 · see citing works
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van Sonderen, A., Thijs, R. D., Coenders, E. C., Jiskoot, L. C., Sánchez, E., de Bruijn, M. A. A. M., van Coevorden‐Hameete, M. H., Wirtz, P. W., Schreurs, M. W. J., Smitt, P. A. E. S., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000003173 · Cited by 663 · see citing works
Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity
Yashiro, K., & Philpot, B. D. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.07.046 · Cited by 649 · see citing works
“Readers are directed to other recent reviews for a more in-depth perspective on the functions and regulation of NMDARs (CullCandy and Leszkiewicz, 2004; Kopp et al., 2007; Lau and Zukin, 2007) and for additional hypotheses regarding the induction of metaplasticity (Abraham, 2008).”
BackgroundDalmau, J. O., Geis, C., & Graus, F. (2017) · Physiological Reviews · doi:10.1152/physrev.00010.2016 · Cited by 631 · see citing works
Structure, function, and allosteric modulation of NMDA receptors
Hansen, K. B., Yi, F., Perszyk, R. E., Furukawa, H., Wollmuth, L. P., Gibb, A. J., & Traynelis, S. F. (2018) · The Journal of General Physiology · doi:10.1085/jgp.201812032 · Cited by 574 · see citing works
The dual role of the extracellular matrix in synaptic plasticity and homeostasis
Dityatev, A., Schachner, M., & Sonderegger, P. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2898 · Cited by 559 · see citing works
Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516 · see citing works
“Dysregulation of these processes can impact channel function and expression and alter synaptic transmission [298, 299].”
BackgroundEpileptogenesis in the immature brain: emerging mechanisms
Rakhade, S. N., & Jensen, F. E. (2009) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.80 · Cited by 554 · see citing works
Milnerwood, A. J., Gladding, C. M., Pouladi, M. A., Kaufman, A. M., Hines, R. M., Boyd, J. D., Ko, R. W. Y., Vasuta, O. C., Graham, R. K., Hayden, M. R., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.008 · Cited by 516 · see citing works
Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons
Yang, J., Ruchti, E., Petit, J.-M., Jourdain, P., Grenningloh, G., Allaman, I., & Magistretti, P. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322912111 · Cited by 504 · see citing works
“In particular, a major role of glycogen-derived L-lactate in LTM and LTP in a hippocampalbased cognitive process such as IA has been demonstrated (1).”
BackgroundHuman N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice
Planagumà, J., Leypoldt, F., Mannara, F., Cuesta, J., Martín‐García, E., Aguilar, E., Titulaer, M. J., Petit‐Pedrol, M., Jain, A., Balice‐Gordon, R. J., et al. (2014) · Brain · doi:10.1093/brain/awu310 · Cited by 489 · see citing works
“…learning, and behaviour depend on the proper function of the excitatory glutamate N-methyl D-aspartate receptor (NMDAR) and a-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptor (AMPAR) and underlying mechanisms of synaptic plasticity (Lau and Zukin, 2007; Shepherd and Huganir, 2007).”
Molecular basis of NMDA receptor functional diversity
Paoletti, P. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07628.x · Cited by 446 · see citing works
“…to the extracellular domains, the Cterminal tails of NMDAR subunits are unlikely to form a well-defined structure but rather contain a series of short motifs that interact with intracellular factors involved in receptor trafficking, anchoring and signaling (Lau & Zukin, 2007; Ryan et al., 2008).”
BackgroundCommunication Between the Synapse and the Nucleus in Neuronal Development, Plasticity, and Disease
Cohen, S., & Greenberg, M. E. (2008) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.24.110707.175235 · Cited by 400 · see citing works
“NMDA receptors are heteromeric channels composed of NR1 and NR2 subunits, with alternative splicing of the NR1 subunit, multiple NR2 isoforms, and developmental regulation of subunit incorporation providing complex regulation of channel composition (Lau & Zukin 2007).”
MethodTau Protein Modifications and Interactions: Their Role in Function and Dysfunction
Mietelska‐Porowska, A., Wasik, U., Goras, M., Filipek, A., & Niewiadomska, G. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15034671 · Cited by 407 · see citing works
“polarized cargo trafficking pathways in neurons [242–244].”
Jackson, A. C., & Nicoll, R. A. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.007 · Cited by 410 · see citing works
The dendritic tree and brain disorders
Kulkarni, V. A., & Firestein, B. L. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.03.005 · Cited by 390 · see citing works
Synaptic plasticity of NMDA receptors: mechanisms and functional implications
Hunt, D. L., & Castillo, P. E. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.01.007 · Cited by 380 · see citing works
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“To investigate whether SNI also affects the synaptic plasticity in the two regions differentially, we next tested the effect of SNI on the NMDA/AMPA ratio, which reflects synaptic plasticity (Lau and Zukin, 2007), in hippocampal and spinal slices with whole-cell patch-clamp recordings.”
BackgroundFehrentz, T., Schönberger, M., & Trauner, D. H. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201103236 · Cited by 376 · see citing works
Acute mechanisms underlying antibody effects in anti–N‐methyl‐D‐aspartate receptor encephalitis
Moscato, E. H., Peng, X., Jain, A., Parsons, T. D., Dalmau, J. O., & Balice‐Gordon, R. J. (2014) · Annals of Neurology · doi:10.1002/ana.24195 · Cited by 361 · see citing works
“Glutamatergic transmission is central to many functions thought to depend on synaptic plasticity, including learning and memory, cognition, and behavior.(1,2) Several newly described immune-mediated encephalitides that target synaptic antigens have offered novel insights into the link between synapse function and huma…”
BackgroundGlutamate receptor dynamics in dendritic microdomains.
Newpher, T. M., & Ehlers, M. D. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.030 · Cited by 356 · see citing works
PSD95: A synaptic protein implicated in schizophrenia or autism?
Coley, A. A., & Gao, W. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.11.016 · Cited by 354 · see citing works
“NMDA receptor hypofunction is highly associated with the pathophysiology of SCZ (Lau and Zukin, 2007; Snyder et al., 2013).”
BackgroundSynapse Pathology in Psychiatric and Neurologic Disease
van Spronsen, M., & Hoogenraad, C. C. (2010) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-010-0104-8 · Cited by 345 · see citing works
“Moreover, alterations in synaptic receptor trafficking, abnormal spine morphology, and defects in synaptic function have been reported in animal models of neuropsychiatric disorders including addiction and schizophrenia [8, 34 ], as well as in models of mental retardation, such as FXS [35].”
BackgroundDisrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis
Mikasova, L., De Rossi, P., Bouchet, D., Georges, F., Rogemond, V., Didelot, A., Meissirel, C., Honnorat, J., & Groc, L. (2012) · Brain · doi:10.1093/brain/aws092 · Cited by 341 · see citing works
“In the basal conditions, GluN2A-NMDA receptors directly interact with intracellular PDZ domain-containing scaffold proteins (Lau and Zukin, 2007) and transmembrane EPHB2Rs (Dalva et al., 2000), leading to a high synaptic retention of NMDA receptors.”
BackgroundJanke, C., & Kneussel, M. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.05.001 · Cited by 335 · see citing works
Reactive Nitrogen Species: Molecular Mechanisms and Potential Significance in Health and Disease
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“170).”
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MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction
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Epigenetic principles and mechanisms underlying nervous system functions in health and disease
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“…and local mRNA translation, and these processes may, in turn, be further regulated by feedback modulation from RBPs and by associated intracellular trafficking of excitatory receptors (Bramham and Wells, 2007; Dahm et al., 2007; Eulalio et al., 2007; Lau and Zukin, 2007; Mehler and Mattick, 2007).”
BackgroundRole of the brain‐derived neurotrophic factor at glutamatergic synapses
Carvalho, A. L., Caldeira, M. V., Santos, S. D., & Duarte, C. B. (2008) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707509 · Cited by 290 · see citing works
“N-Methyl-D-aspartate receptors are relatively stable at the synapse when compared to AMPARs, but recent evidences indicate that NMDA receptors are internalized in a regulated manner (for a review, see Lau and Zukin, 2007).”
BackgroundInfluentialInfluence 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 CTD contains specific binding motifs for intracellular trafficking and signalling proteins, scaffold proteins and several phosphorylation sites (Lau and Zukin, 2007; Salter and Kalia, 2004).”
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Ubiquitination in postsynaptic function and plasticity
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“OF INHIBITORY SYNAPSES Similar to glutamate receptors (Kennedy & Ehlers 2006, Lau & Zukin 2007, Newpher & Ehlers 2008, Shepherd & Huganir 2007), γamino butyric acid (GABA) receptors undergo regulated trafficking and lysosomal degradation.”
NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2
Girouard, H., Wang, G., Gallo, E. F., Anrather, J., Zhou, P., Pickel, V. M., & Iadecola, C. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0133-09.2009 · Cited by 254 · see citing works
“One of the main functions of the NMDA receptor is synaptic plasticity, a phenomenon thought to underlie learning and memory (Lau and Zukin, 2007).”
BackgroundWhich way to go? Cytoskeletal organization and polarized transport in neurons
Kapitein, L. C., & Hoogenraad, C. C. (2010) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2010.08.015 · Cited by 246 · see citing works
Anti-NMDA-receptor encephalitis: A severe, multistage, treatable disorder presenting with psychosis
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“Localized in post-synaptic membranes, these receptors serve as ligand-gated cation channels with major significance for synaptic transmission and plasticity (Bliss and Collingridge, 1993; Lau and Zukin, 2007; Yashiro and Philpot, 2008).”
BackgroundNMDA hypofunction as a convergence point for progression and symptoms of schizophrenia
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“It is likely that convergent mechanisms target NMDAR, which in turn contribute to negative symptoms and neurocognitive dysfunction directly (Lau and Zukin, 2007), as well as to positive symptoms via dysregulation of brain DA systems indirectly (Howes and Kapur, 2009; Abi-Dargham, 2012).”
BackgroundPlasticity and injury in the developing brain
Johnston, M. V., Ishida, A., Nakajima, W., Matsushita, H., Nishimura, A., & Tsuji, M. (2008) · Brain and Development · doi:10.1016/j.braindev.2008.03.014 · Cited by 230 · see citing works
“Synaptic plasticity is the most important mechanism that allows the developing brain to adapt to environmental influences and store information throughout life [3].”
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“The UPS system is disrupted in several other CNS disorders including Parkinson’s disease, schizophrenia, and Huntington’s disease (Altar et al., 2005; Lim and Tan, 2007; Dunah et al., 2000; Lau and Zukin, 2007).”
BackgroundCasein Kinase 2 Regulates the NR2 Subunit Composition of Synaptic NMDA Receptors
Sanz-Clemente, A., Matta, J. A., Isaac, J. T. R., & Roche, K. W. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.011 · Cited by 224 · see citing works
“NMDARs play important roles in development, learning and memory, as well as in some neuropsychiatric disorders (Lau and Zukin, 2007).”
Dual Palmitoylation of NR2 Subunits Regulates NMDA Receptor Trafficking
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NMDA receptor subunit composition controls synaptogenesis and synapse stabilization
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“Disruption of this balance has been linked to abnormal brain development and neuropsychiatric disorders such as Alzheimer’s disease and schizophrenia (3).”
BackgroundEmerging roles of GluN3-containing NMDA receptors in the CNS
Pérez-Otaño, I., Larsen, R. S., & Wesseling, J. F. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.92 · Cited by 214 · see citing works
Reduced prefrontal-parietal effective connectivity and working memory deficits in schizophrenia
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“Synaptic plasticity is strongly related to glutamatergic neurotransmission and its modulation by other transmitter systems (Lau and Zukin, 2007).”
BackgroundNaylor, D. E., Liu, H., Niquet, J., & Wasterlain, C. G. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.12.015 · Cited by 215 · see citing works
“, 2004), degenerative disorders (Chen et al., 1999c; Lau and Zukin, 2007; Snyder et al., 2005), and excitotoxicity/cell death (DeRidder et al.”
BackgroundMatrix Metalloproteinase-9 Controls NMDA Receptor Surface Diffusion through Integrin β1 Signaling
Michaluk, P., Mikasová, L., Groc, L., Frischknecht, R., Choquet, D., & Kaczmarek, L. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5346-08.2009 · Cited by 204 · see citing works
NMDA Receptors in the Central Nervous System
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“NMDA receptors have been considered in the context of numerous neurological conditions, either as a potential causative feature, exacerbating component, or therapeutic target [23,1,2,427,42].”
BackgroundInfluentialExtrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices
Harris, A. Z., & Pettit, D. L. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.137679 · Cited by 202 · see citing works
“In addition, NMDARs have recently been shown to dynamically traffic in response to neuronal activity providing an alternate mechanism for modulation of synaptic strength (Lau & Zukin, 2007).”
BackgroundMetabotropic glutamate receptor-dependent long-term potentiation
Anwyl, R. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.01.002 · Cited by 201 · see citing works
Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression
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“homer synaptic clusters is driven by soluble beta-amyloid(1-40) through divergent NMDAR-dependent signalling pathways.”
BackgroundThe role of metaplasticity mechanisms in regulating memory destabilization and reconsolidation
Finnie, P. S. B., & Nader, K. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.03.008 · Cited by 189 · see citing works
Mechanisms 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
Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion
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“This result suggested that there was an intracellular pool of NMDARs primed for surface recruitment in response to appropriate signals, similar to the situation in neurons (Lau and Zukin, 2007).”
Matta, J. A., Ashby, M. C., Sanz-Clemente, A., Roche, K. W., & Isaac, J. T. R. (2011) · Neuron · doi:10.1016/j.neuron.2011.02.045 · Cited by 191 · see citing works
A Silent Synapse-Based Mechanism for Cocaine-Induced Locomotor Sensitization
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“Cocaine-induced synapses, like immature synapses, are enriched in the immature, NR2B-containing form of NMDARs (Dingledine et al., 1999; Washbourne et al., 2002; Groc et al., 2006; Lau and Zukin, 2007).”
BackgroundSelf-citationStrait, D. L., & Kraus, N. (2013) · Hearing Research · doi:10.1016/j.heares.2013.08.004 · Cited by 191 · see citing works
“NMDA glutamate receptors facilitate the experience-dependent synaptic plasticity that undergirds learning by increasing synaptic efficacy (for review see Lau and Zukin, 2007).”
Goebel-Goody, S. M., Davies, K. D., Linger, R. M. A., Freund, R. K., & Browning, M. D. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.11.006 · Cited by 189 · see citing works
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Metaplasticity at Single Glutamatergic Synapses
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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
Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy
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“Postsynaptic NMDA receptor trafficking is of particular importance to synapse maturation and plasticit”
BackgroundPresynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity
Corlew, R., Brasier, D. J., Feldman, D. E., & Philpot, B. D. (2008) · The Neuroscientist · doi:10.1177/1073858408322675 · Cited by 185 · see citing works
De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability
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Calcium Signaling in Dendritic SpinesPreprint
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“Because changes in mRNA do not necessarily predict changes in protein, we examined protein levels of three REST targets (GluA2, GluN1, and GluN2B) known to play roles in neuronal death in postischemic CA1 (33, 34).”
BackgroundSelf-citationNon‐synaptic receptors and transporters involved in brain functions and targets of drug treatment
Vizi, E. S., Fekete, Á., Károly, R., & Mike, Á. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00624.x · Cited by 182 · see citing works
“The finding of endocytic zones on spines lateral from synapse (Blanpied et al., 2002) reveal that lateral diffusion of receptors between synapse and nonsynaptic regions may be the part of the process of receptor recycling (Lau and Zukin, 2007).”
BackgroundInfluentialPalmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking
Thomas, G. M., Hayashi, T., Chen, C.-M., Chiu, S.-L., & Huganir, R. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.021 · Cited by 181 · see citing works
“(Shepherd and Huganir, 2007; Newpher and Ehlers, 2008; Lau and Zukin, 2007).”
Budreck, E. C., Kwon, O.-B., Jung, J. H., Baudouin, S. J., Thommen, A., Kim, H.-S., Fukazawa, Y., Harada, H., Tabuchi, K., Shigemoto, R., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214718110 · Cited by 181 · see citing works
Molecular evolution of genes in avian genomes
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“GRIN2a encodes a subunit of the Nmethyl-D-aspartate (NMDA) receptor, a subtype of ionotropic glutamate-gated ion channel that has well-established roles in learning and brain plasticity (reviewed in [86]).”
BackgroundNg, D., Pitcher, G. M., Szilard, R. K., Sertie, A. L., Kanisek, M., Clapcote, S. J., Lipina, T. V., Kalia, L. V., Joo, D. T., McKerlie, C., et al. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000041 · Cited by 180 · see citing works
“of NMDARs [41–43].”
Beyond the Cholinergic Hypothesis: Do Current Drugs Work in Alzheimer's Disease?
Martorana, A., Esposito, Z., & Koch, G. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00175.x · Cited by 174 · see citing works
“mediate toxic effects of glutamate [113,114].”
Allosteric modulators of NMDA receptors: multiple sites and mechanisms
Zhu, S., & Paoletti, P. (2014) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2014.10.009 · Cited by 167 · see citing works
“Importantly, the molecular composition of NMDARs is not static but varies in an experience-dependent and activity-dependent manner, or in disease states, with profound consequences on network function [2,9].”
BackgroundInfluence of the NR3A subunit on NMDA receptor functions
Henson, M. A., Roberts, A. C., Pérez‐Otaño, I., & Philpot, B. D. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.004 · Cited by 170 · see citing works
E-I balance and human diseases – from molecules to networking
Eichler, S. A. (2008) · Frontiers in Molecular Neuroscience · doi:10.3389/neuro.02.002.2008 · Cited by 165 · see citing works
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“complex and leads to the stabilization of receptors on the cell surface, increasing synaptic efficiency (for reviews see Kopp et al., 2007; Chen and Roche, 2007; Lau and Zukin, 2007).”
BackgroundDecker, H., Jürgensen, S., Adrover, M. F., Brito‐Moreira, J., Bomfim, T. R., Klein, W. L., Epstein, A. L., Felice, F. G. D., Jerusalinsky, D. A., & Ferreira, S. T. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07058.x · Cited by 164 · see citing works
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“…Cdk5 inhibition regulates the surface expression of NMDARs by increasing the levels of phosphorylation of Y1472 NR2B, suggesting a mechanism by which Cdk5 activity impacts the A -dependent effect on NMDARs and the synaptic dysfunction observed in Alzheimer’s (Selkoe, 2002; Lau and Zukin, 2007).”
BackgroundActivity‐dependent synaptic plasticity of NMDA receptors
Rebola, N., Srikumar, B. N., & Mulle, C. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.179382 · Cited by 166 · see citing works
“The C-terminus of both NR1 and NR2 subunits interacts with several intracellular scaffolding proteins, is subject to phosphorylation, and as such is involved in the regulation of receptor trafficking and function (Salter & Kalia, 2004; Lau & Zukin, 2007; Groc et al. 2009).”
BackgroundInfluentialEphB Controls NMDA Receptor Function and Synaptic Targeting in a Subunit-Specific Manner
Nolt, M. J., Lin, Y., Hruska, M., Murphy, J. A., Sheffler-Collins, S. I., Kayser, M. S., Passer, J. Z., Bennett, M. V. L., Zukin, R. S., & Dalva, M. B. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0282-11.2011 · Cited by 161 · see citing works
“NMDARs are recruited to and retained at synapses through well studied mechanisms (Pérez-Otaño and Ehlers, 2005; Lau and Zukin, 2007), including postsynaptic density-95/Discs large/ zona occludens-1 (PDZ) binding domain interactions and phosphorylation of the receptor itself (Kim and Sheng, 2004; Prybylowski et al.”
BackgroundInfluentialSelf-citationSocial deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression
Chung, W., Choi, S. Y., Lee, E., Park, H., Kang, J., Park, H., Choi, Y., Lee, D., Park, S.-G., Kim, R., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3927 · Cited by 163 · see citing works
A Brief Introduction to the Transduction of Neural Activity into Fos Signal
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“As a glutamate receptor-channel complex, the NMDAR is highly permeable to calcium (Lau & Zukin, 2007).”
BackgroundIdentification of blood biomarkers for psychosis using convergent functional genomics
Kurian, S. M., Le-Niculescu, H., Patel, S. D., Bertram, D., Davis, J. P., Dike, C., Yehyawi, N., Lysaker, P. H., Dustin, J., Caligiuri, M. P., et al. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.117 · Cited by 162 · see citing works
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“Synaptic vs extrasynaptic location of NMDARs critically alters receptor function and signaling pathway activation (Groc et al, 2009; Hardingham and Bading, 2010; Hardingham et al, 2002; Ivanov et al, 2006; Lau and Zukin, 2007).”
BackgroundMAGUKs: multifaceted synaptic organizers
Won, S., Levy, J. M., Nicoll, R. A., & Roche, K. W. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.01.006 · Cited by 155 · see citing works
“All family members bind directly to GluN2 subunits of NMDARs thereby stabilizing NMDARs at the cell surface [15].”
BackgroundAMPA receptors as drug targets in neurological disease—advantages, caveats, and future outlook
Chang, P. K. ‐., Verbich, D., & McKinney, R. A. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08165.x · Cited by 155 · see citing works
- Authors
- Lau, C. G., & Zukin, R. S.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Zukin, R. Suzanne
- Venue
- Nature Reviews Neuroscience
- Published
- 2007-06
- Volume
- 8
- Issue
- 6
- Pages
- 413-426
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- OpenAlex
- W1985241009
- Cited by
- 1,159
- References
- 154
- Citations by year
- 2026: 27 · 2025: 27 · 2024: 35 · 2023: 50 · 2022: 39 · 2021: 60 · 2020: 54 · 2019: 70 · 2018: 75 · 2017: 66 · 2016: 51 · 2015: 78 · 2014: 70 · 2013: 69 · 2012: 89
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS-20752, R01NS020752)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- NMDA receptor, receptor trafficking, synaptic plasticity, postsynaptic density, receptor subunit composition, synaptic targeting, endolysosomal pathway, extrasynaptic receptors, activity-dependent regulation, cocaine dependence, Alzheimer's disease, schizophrenia, neuropsychiatric disorders
- MeSH terms
- Animals, Mental Disorders, Brain, Endocytosis, Humans, Synaptic Transmission, Neuronal Plasticity, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Protein Transport
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