AccScience Publishing / AN / Volume 1 / Issue 2 / DOI: 10.36922/an.v1i2.148
Cite this article
119
Download
1817
Views
Journal Browser
Volume | Year
Issue
Search
News and Announcements
View All
REVIEW

NMDA receptors: Biological properties and their roles in neuropsychiatric disorders

Qing-Qing Li1* Xiao Lin2 Yun Stone Shi1,2
Show Less
1 State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Department of Neurology, Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210032, China
2 Guangdong Institute of Intelligence Science and Technology, Zhuhai 519031, China
Advanced Neurology 2022, 1(2), 148 https://doi.org/10.36922/an.v1i2.148
Submitted: 4 July 2022 | Accepted: 12 August 2022 | Published: 29 August 2022
© 2022 by the Authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Proper signal transmission is the fundamental process of the brain activity. Changes and adaption of neuroplasticity based on the strength of synaptic transmission are essential for the information propagation in the central nervous system, which contribute to cognition, learning, and memory. Being the major excitatory neurotransmitter in the central nervous system, glutamate acts primarily through binding to the glutamate receptors, the glutamate-gated ion channels localized on post-synaptic membrane. The ionotropic glutamate receptors, pharmacologically grouped into α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, N-methyl-D-aspartic acid (NMDA) receptors, and kainate receptors, have been shown to play distinct roles in excitatory neurotransmission and synaptic plasticity. Due to their high permeability to Ca2+, the NMDA receptors have very unique function in neurotransmission and particular importance in the induction of long-term synaptic plasticity. Dysfunction of NMDA receptors causes impairment in synaptic plasticity and learning and memory. In recent years, with the development of genome-wide association studies and next-generation sequencing technology, mutations of NMDA receptor subunits have been in a variety of neuropsychiatric disorders, such as cognitive impairment, schizophrenia, autism or epilepsy. In clinical practice, NMDA receptors are known as the targets for the treatment of many neuropsychiatric disorders. In current review, we summarize current knowledge of NMDA receptors with different subunit compositions in the context of expression pattern, channel properties, protein trafficking, and synaptic plasticity as well as their roles in neuropsychiatric disorders.

Keywords
NMDA receptor
Ion channel
Protein trafficking
Synaptic plasticity
Neuropsychiatric disorders
Funding
National Key R&D Program of China
National Natural Science Foundation of China
Natural Science Foundation of Jiangsu Province
Special Fund for Science and Technology Innovation Strategy of Guangdong Province
Fundamental Research Funds for the Central Universities
References
[1]

Traynelis SF, Wollmuth LP, McBain CJ, et al., 2010, Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol Rev, 62(3): 405–496. https://doi.org/10.1124/pr.109.002451

[2]

Alzheimer’s Association, 2022, 2022 Alzheimer’s disease facts and figures. Alzheimers Dement, 18(4): 700–789. https://doi.org/10.1002/alz.12638

[3]

Avila J, Perry GA, 2021, Multilevel view of the development of Alzheimer’s disease. Neuroscience, 457: 283–293. https://doi.org/10.1016/j.neuroscience.2020.11.015

[4]

Christensen DL, Baio J, Braun KV, et al., 2018, Prevalence and characteristics of autism spectrum disorder among children aged 8 year autism and developmental disabilities monitoring network, 11 sites, United States, 2012. Morb Mort Wkly Rep, 65: 1–23. https://doi.org/10.15585/mmwr.ss6513a1

[5]

Lord C, Brugha TS, Charman T, et al., 2020, Autism spectrum disorder. Nat Rev Dis Primers, 6(1): 5. https://doi.org/10.1038/s41572-019-0138-4

[6]

Anderson RM, Hadjichrysanthou C, Evans S, et al., 2017, Why do so many clinical trials of therapies for Alzheimer’s disease fail? Lancet, 390: 2327–2329. https://doi.org/10.1016/S0140-6736(17)32399-1 

[7]

Mitsumoto H, Brooks BR, Silani V, 2014, Clinical trials in amyotrophic lateral sclerosis: Why so many negative trials and how can trials be improved? Lancet Neurol, 13: 1127–1138. https://doi.org/10.1016/S1474-4422(14)70129-2 

[8]

Henriquez F, Cabello V, Baez S, et al., 2021, Multidimensional clinical assessment in frontotemporal dementia and its spectrum in latin America and the Caribbean: A narrative review and a glance at future challenges. Front Neurol, 12: 768591. https://doi.org/10.3389/fneur.2021.768591

[9]

Panza, F, Solfrizzi V, Seripa D, et al., 2015, Progresses in treating agitation: A major clinical challenge in Alzheimer’s disease. Expert Opin Pharmacother, 16: 2581–2588. https://doi.org/10.1517/14656566.2015.1092520

[10]

Song J, Patel RV, Sharif M, et al., 2022, Chemogenetics as a neuromodulatory approach to treating neuropsychiatric diseases and disorders. Mole Ther, 30: 990–1005. https://doi.org/10.1016/j.ymthe.2021.11.019 

[11]

Thompson PM, Andreassen OA, Arias-Vasquez A, et al., 2017, ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide. NeuroImage, 145(Pt B): 389–408. https://doi.org/10.1016/j.neuroimage.2015.11.057 

[12]

Schang AL, Saberan-Djoneidi D, Mezger V, 2018, The impact of epigenomic next-generation sequencing approaches on our understanding of neuropsychiatric disorders. Clin Genet, 93(3): 467–480. https://doi.org/10.1111/cge.13097 

[13]

Dorado G, Galvez S, Rosales TE, et al., 2021, Analyzing modern biomolecules: The revolution of nucleic-acid sequencing review. Biomolecules, 11(8): 1111. https://doi.org/10.3390/biom11081111 

[14]

Dehghan A, 2018, Genome-wide association studies. Methods Mol Biol, 1793: 37–49. https://doi.org/10.1007/978-1-4939-7868-7_4 

[15]

Qin Y, Du Y, Chen L, et al., 2022, A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling. Mole Psychiatry, 27(7): 2985–2998. https://doi.org/10.1038/s41380-022-01539-1 

[16]

Peng SX, Pei J, Ge Y, et al., 2022, Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human. Mol Psychiatry, Online ahead of print. https://doi.org/10.1038/s41380-022-01659-8

[17]

Li QQ, Chen J, Hu P, et al., 2022, Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory. Mol Psychiatry, Online ahead of print. https://doi.org/10.1038/s41380-022-01579-7

[18]

Teng XY, Hu P, Chen Y, et al., 2022, A novel Lgi1 mutation causes white matter abnormalities and impairs motor coordination in mice. FASEB J, 36: e22212. https://doi.org/10.1096/fj.202101652R

[19]

Hall J, Bray NJ, 2022, Schizophrenia genomics: Convergence on synaptic development, adult synaptic plasticity, or both? Biol Psychiatry, 91(8): 709–717. https://doi.org/10.1016/j.biopsych.2021.10.018

[20]

Ding YD, Chen X, Guo WB, et al., 2022, Reduced nucleus accumbens functional connectivity in reward network and default mode network in patients with recurrent major depressive disorder. Transl Psychiatry, 12: 236. https://doi.org/10.1038/s41398-022-01995-x

[21]

Paoletti P, 2011, Molecular basis of NMDA receptor functional diversity. Eur J Neurosci, 33: 1351–1365. https://doi.org/10.1111/j.1460-9568.2011.07628.x

[22]

Cull-Candy SG, Leszkiewicz DN, 2004, Role of distinct NMDA receptor subtypes at central synapses. Sci STKE, 2004(255): re16. https://doi.org/10.1126/stke.2552004re16

[23]

Rumbaugh G, Prybylowski K, Wang JF, et al., 2000, Exon 5 and spermine regulate deactivation of NMDA receptor subtypes. J Neurophysiol, 83: 1300–1306. https://doi.org/10.1152/jn.2000.83.3.1300

[24]

Vance KM, Hansen KB, Traynelis SF, 2012, GluN1 splice variant control of GluN1/GluN2D NMDA receptors. J Physiol, 590(16): 3857–3875. https://doi.org/10.1113/jphysiol.2012.234062

[25]

Horak M, Wenthold RJ, 2009, Different roles of C-terminal cassettes in the trafficking of full-length NR1 subunits to the cell surface. J Biol Chem, 284(15): 9683–9691. https://doi./org/10.1074/jbc.M807050200

[26]

Paoletti P, Bellone C, Zhou Q, 2013, NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci, 14: 383–400. https://doi.org/10.1038/nrn3504 

[27]

Mayer ML, 2011, Emerging models of glutamate receptor ion channel structure and function. Structure, 19(10): 1370–1380. https://doi.org/10.1016/j.str.2011.08.009

[28]

Won S, Incontro S, Nicoll RA, et al., 2016, PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61. Proc Natl Acad Sci U S A, 113: E4736–E4744. https://doi.org/10.1073/pnas.1609702113

[29]

Incontro S, Díaz-Alonso J, Iafrati J, et al., 2019, The CaMKII/ NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms. Nat Commun, 9(1): 2069. https://doi.org/10.1038/s41467-018-04439-7

[30]

Karakas E, Furukawa H, 2014, Crystal structure of a heterotetrameric NMDA receptor ion channel. Science, 344: 992–997. https://doi.org/10.1126/science.1251915

[31]

Lee CH, Lü W, Michel JC, et al., 2014, NMDA receptor structures reveal subunit arrangement and pore architecture. Nature, 511(7508): 191–197. https://doi.org/10.1038/nature13548

[32]

Meyerson JR, Kumar J, Chittori S, et al., 2014, Structural mechanism of glutamate receptor activation and desensitization. Nature, 514(7522): 328–334. https://doi.org/10.1038/nature13603 

[33]

Sobolevsky AI, 2015, Structure and gating of tetrameric glutamate receptors. J Physiol, 593(1): 29–38. https://doi.org/10.1113/jphysiol.2013.264911

[34]

Tajima N, Karakas E, Grant T, et al., 2016, Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature, 534(7605): 63–68. https://doi.org/10.1038/nature17679

[35]

Zhu S, Stein RA, Yoshioka C, et al., 2016, Mechanism of NMDA receptor inhibition and activation. Cell, 165(3): 704–714. https://doi.org/10.1016/j.cell.2016.03.028

[36]

Romero-Hernandez A, Simorowski N, Karakas E, et al., 2016, Molecular basis for subtype specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino-terminal domain. Neuron, 92(6): 1324–1336. https://doi.org/10.1016/j.neuron.2016.11.006

[37]

Furukawa H, Singh SK, Mancusso R, et al., 2005, Subunit arrangement and function in NMDA receptors. Nature, 438(7065): 185–192. https://doi.org/10.1038/nature04089

[38]

Hackos DH, Lupardus PJ, Grand T, et al., 2016, Positive allosteric modulators of GluN2A-containing NMDARs with distinct modes of action and impacts on circuit function. Neuron, 89(5): 983–999. https://doi.org/10.1016/j.neuron.2016.01.016

[39]

Volgraf M, Sellers BD, Jiang Y, et al., 2016, Discovery of GluN2A-selective NMDA receptor positive allosteric modulators (PAMs): Tuning deactivation kinetics via structure-based design. J Med Chem, 59(6): 2760–2779. https://doi.org/10.1021/acs.jmedchem.5b02010 

[40]

Yi F, Mou TC, Dorsett KN, et al., 2016, Structural basis for negative allosteric modulation of GluN2A-Containing NMDA receptors. Neuron, 91(6): 1316–1329. https://doi.org/10.1016/j.neuron.2016.08.014

[41]

Jones KS, Van Dongen HM, Van Dongen AM, 2002, The NMDA receptor M3 segment is a conserved transduction element coupling ligand binding to channel opening. J Neurosci, 22(6): 2044–2053. https://doi.org/10.1523/JNEUROSCI.22-06-02044.2002

[42]

Yuan H, Erreger K, Dravid SM, et al., 2005, Conserved structural and functional control of N-methyl-D-aspartate receptor gating by transmembrane domain M3. J Biol Chem, 280(33): 29708–29716. https://doi.org/10.1074/jbc.M414215200

[43]

Chang HR, Kuo CC, 2008, The activation gate and gating mechanism of the NMDA receptor. J Neurosci, 28(7): 1546–1556. https://doi.org/10.1523/JNEUROSCI.3485-07.2008

[44]

Twomey EC, Sobolevsky AI, 2018, Structural mechanisms of gating in ionotropic glutamate receptors. Biochemistry, 57(3): 267–276. https://doi.org/10.1021/acs.biochem.7b00891

[45]

Gibb AJ, Ogden KK, McDaniel MJ, et al., 2018, A structurally derived model of subunit-dependent NMDA receptor function. J Physiol, 596(17): 4057–4089. https://doi.org/10.1113/JP276093

[46]

Watanabe M, Inoue Y, Sakimura K, et al., 1992, Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport, 3(12): 1138–1140. https://doi.org/10.1097/00001756-199212000-00027

[47]

Akazawa C, Shigemoto R, Bessho Y, et al., 1994, Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J Comp Neurol, 347(1): 150–160. https://doi.org/10.1002/cne.903470112

[48]

Monyer H, Burnashev N, Laurie DJ, et al., 1994, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron, 12(3): 529–540. https://doi.org/10.1016/0896-6273(94)90210-0

[49]

Laurie DJ, Seeburg PH, 1994, Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J Neurosci, 14(5): 3180–3194. https://doi.org/10.1523/JNEUROSCI.14-05-03180.1994

[50]

Ishii T, Moriyoshi K, Sugihara H, et al., 1993, Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. J Biol Chem, 268(4): 2836–2843. 

[51]

Sheng M, Cummings J, Roldan LA, et al., 1994, Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature, 368(6467): 144–147. https://doi.org/10.1038/368144a0

[52]

Henson MA, Roberts AC, Perez-Otano I, et al., 2010, Influence of the NR3A subunit on NMDA receptor functions. Prog Neurobiol, 91: 23–37. https://doi.org/10.1016/j.pneurobio.2010.01.004

[53]

Pachernegg S, Strutz-Seebohm N, Hollmann M, 2012, GluN3 subunit-containing NMDA receptors: Not just one-trick ponies. Trends Neurosci, 35(4): 240–249. https://doi.org/10.1016/j.tins.2011.11.010

[54]

Johnson JW, Ascher P, 1987, Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature, 325(6104): 529–531. https://doi.org/10.1038/325529a0

[55]

Kleckner NW, Dingledine R, 1988, Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science, 241(4867): 835–837. https://doi.org/10.1126/science.284175

[56]

Watkins JC, Evans RH, 1981, Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol, 21: 165–204. https://doi.org/10.1146/annurev.pa.21.040181.001121

[57]

Patneau DK, Mayer ML, 1990, Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J Neurosci, 10(7): 2385–2399. https://doi.org/10.1523/JNEUROSCI.10-07-02385.199

[58]

Clements JD, Westbrook GL, 1991, Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron, 7(4): 605–613. https://doi.org/10.1016/0896-6273(91)90373-8 

[59]

Chatterton JE, Awobuluyi M, Premkumar LS, et al., 2002, Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature, 415(6873): 793–798. https://doi.org/10.1038/nature715 

[60]

Iijima K, Takase S, Tsumuraya K, et al., 1978, Changes in free amino acids of cerebrospinal fluid and plasma in various neurological diseases. Tohoku J Exp Med, 126(2): 133–150. https://doi.org/10.1620/tjem.126.133

[61]

Papouin T, Ladépêche L, Ruel J, et al., 2012, Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell, 150(3): 633–646. https://doi.org/10.1016/j.cell.2012.06.029 

[62]

Erreger K, Geballe MT, Kristensen A, et al., 2007, Subunit-specific agonist activity at NR2A, NR2B-, NR2C, and NR2D-containing N-methyl-D-aspartate glutamate receptors. Mol Pharmacol, 72(4): 907–920. https://doi.org/10.1124/mol.107.037333

[63]

Madry C, Betz H, Geiger JR, et al., 2010, Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves ca-dependent outward rectification. Front Mol Neurosci, 3: 6. https://doi.org/10.3389/fnmol.2010.00006

[64]

Ulbrich MH, Isacoff EY, 2007, Subunit counting in membrane-bound proteins. Nat Methods, 4(4): 319–321. https://doi.org/10.1038/nmeth1024

[65]

Ulbrich MH, Isacoff EY, 2008, Rules of engagement for NMDA receptor subunits. Proc Natl Acad Sci U S A, 105(37): 14163–14168.https://doi.org/10.1073/pnas.0802075105

[66]

Awobuluyi M, Yang J, Ye Y, et al., 2007, Subunit-specific roles of glycine-binding domains in activation of NR1/ NR3 N-methyl-D-aspartate receptors. Mol Pharmacol, 71(1): 112–122. https://doi.org/10.1124/mol.106.030700

[67]

Madry C, Mesic I, Nicke A, et al., 2007, Principal role of NR3 subunits in NR1/NR3 excitatory glycine receptor function. Biochem Biophys Res Commun, 354(1): 102–108. https://doi.org/10.1016/j.bbrc.2006.12.153

[68]

Retchless S, Gao B, Johnson J W, 2012, A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction. Nat Neurosci, 15: 406–413, S401–S402. https://doi.org/10.1038/nn.3025

[69]

Chen N, Luo T, Raymond LA, 1999, Subtype-dependence of NMDA receptor channel open probability. J Neurosci, 19(16): 6844–6854. https://doi.org/10.1523/JNEUROSCI.19-16-06844.1999

[70]

Errege K, Dravid SM, Banke TG, et al., 2005, Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J Physiol, 563(Pt 2): 345–358. https://doi.org/10.1113/jphysiol.2004.080028

[71]

Sobczyk A, Scheuss V, Svoboda K, 2005, NMDA receptor subunit-dependent [Ca2+] signaling in individual hippocampal dendritic spines. J Neurosci, 25(26): 6037–6046. https://doi.org/10.1523/JNEUROSCI.1221-05.2005 

[72]

Sprengel R, Suchanek B, Amico C, et al., 1998, Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell, 92(2): 279–289. https://doi.org/10.1016/s0092-8674(00)80921-6

[73]

Martel MA, Ryan TJ, Bell KF, et al., 2012, The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron, 74(3): 543–556. https://doi.org/10.1016/j.neuron.2012.03.021

[74]

Sanz-Clemente A, Nicoll RA, Roche KW, 2013, Diversity in NMDA receptor composition: Many regulators, many consequences. Neuroscientist, 19(1): 62–75. https://doi.org/10.1177/1073858411435129

[75]

Mu Y, Otsuka T, Horton AC, et al., 2003, Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors. Neuron, 40(3): 581–594. https://doi.org/10.1016/s0896-6273(03)00676-7

[76]

Perez-Otano I, Luján R, Tavalin SJ, et al., 2006, Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1. Nat Neurosci, 9(5): 611–621. https://doi.org/10.1038/nn1680

[77]

Horak M, Petralia RS, Kaniakova M, et al., 2014, ER to synapse trafficking of NMDA receptors. Front Cell Neurosci, 8: 394. https://doi./org/10.3389/fncel.2014.00394

[78]

McIlhinney RA, Le Bourdellès B, Molnár E, et al., 1998, Assembly intracellular targeting and cell surface expression of the human N-methyl-D-aspartate receptor subunits NR1a and NR2A in transfected cells. Neuropharmacology, 37(10–11): 1355–1367. https://doi.org/10.1016/s0028-3908(98)00121-x

[79]

Fukaya M, Kato A, Lovett C, et al., 2003, Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc Natl Acad Sci U S A, 100(8): 4855–4860. https://doi.org/10.1073/pnas.0830996100

[80]

Horak M, Chang K, Wenthold RJ, 2008, Masking of the endoplasmic reticulum retention signals during assembly of the NMDA receptor. J Neurosci, 28(13): 3500–3509. https://doi.org/10.1523/JNEUROSCI.5239-07.2008

[81]

Standley S, Roche KW, McCallum J, et al., 2000, PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron, 28(3): 887–898. https://doi.org/10.1016/s0896-6273(00)00161-6

[82]

Scott DB, Blanpied TA, Swanson GT, et al, 2001, An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci, 21(3): 3063–3072. https://doi.org/10.1523/JNEUROSCI.21-09-03063.2001

[83]

Prybylowski K, Fu Z, Losi G, et al., 2002, Relationship between availability of NMDA receptor subunits and their expression at the synapse. J Neurosci, 22(20): 8902–8910. https://doi.org/10.1523/JNEUROSCI.22-20-08902.2002 

[84]

Hawkins LM, Prybylowski K, Chang K, et al., 2004, Export from the endoplasmic reticulum of assembled N-methyl-d-aspartic acid receptors is controlled by a motif in the c terminus of the NR2 subunit. J Biol Chem, 279(28): 28903–28910. https://doi.org/10.1074/jbc.M402599200

[85]

Yang W, Zheng C, Song Q, et al., 2007, A three amino acid tail following the TM4 region of the N-methyl-D-aspartate receptor (NR) 2 subunits is sufficient to overcome endoplasmic reticulum retention of NR1-1a subunit. J Biol Chem, 282(1): 9269–9278. https://doi.org/10.1074/jbc.M700050200

[86]

Sans N, Prybylowski K, Petralia RS, et al., 2003, NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex. Nat Cell Biol, 5(6): 520–530. https://doi.org/10.1038/ncb990

[87]

Sans N, Wang PY, Du Q, et al., 2005, mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nat Cell Biol, 7(12): 1179–1190. https://doi.org/10.1038/ncb1325

[88]

Sans N, Petralia RS, Wang YX, et al., 2000, A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci, 20(3): 1260–1271. https://doi.org/10.1523/JNEUROSCI.20-03-01260.2000 

[89]

Muller BM, Kistner U, Kindler S, et al., 1996, SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo. Neuron, 17(2): 255–265. https://doi.org/10.1016/s0896-6273(00)80157-9 

[90]

Jeyifous O, Waites CL, Specht CG, et al., 2009, SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nat Neurosci, 12(8): 1011-1019. https://doi.org/10.1038/nn.2362

[91]

Setou M, Nakagawa T, Seog DH, et al., 2000, Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science, 288: 1796–1802. https://doi.org/10.1126/science.288.5472.1796

[92]

Guillaud L, Setou M, Hirokawa N, 2003, KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons. J Neurosci, 23(1): 131–140. https://doi.org/10.1523/JNEUROSCI.23-01-00131.2003

[93]

Yin X, Takei Y, Kido MA, et al., 2011, Molecular motor KIF17 is fundamental for memory and learning via differential support of synaptic NR2A/2B levels. Neuron, 70(2): 310–325. https://doi.org/10.1016/j.neuron.2011.02.049

[94]

Lin EI, Jeyifous O, Green WN, 2013, CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors. J Neurosci, 33(29): 12067–12076. https://doi.org/10.1523/JNEUROSCI.0816-13.2013 

[95]

Gardoni F, Mauceri D, Fiorentini C, et al., 2003, CaMKII-dependent phosphorylation regulates SAP97/NR2A interaction. J Biol Chem, 278(45): 44745–44752. https://doi.org/10.1074/jbc.M303576200

[96]

Mauceri D, Gardoni F, Marcello E, et al., 2007, Dual role of CaMKII-dependent SAP97 phosphorylation in mediating trafficking and insertion of NMDA receptor subunit NR2A. J Neurochem, 100(4): 1032–1046. https://doi.org/10.1111/j.1471-4159.2006.04267.x

[97]

Yin X, Feng X, Takei Y, et al., 2012, Regulation of NMDA receptor transport: A KIF17-cargo binding/releasing underlies synaptic plasticity and memory in vivo. J Neurosci, 32: 5486–5499. https://doi.org/10.1523/JNEUROSCI.0718-12.2012

[98]

Thomas GM, Huganir RL, 2013, Palmitoylation-dependent regulation of glutamate receptors and their PDZ domain-containing partners. Biochem Soc Trans, 41: 72–78. https://doi.org/10.1042/BST20120223

[99]

Lussier MP, Sanz-Clemente A, Roche KW, 2015, Dynamic regulation of N-Methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by posttranslational modifications. J Biol Chem, 290: 28596–28603. https://doi.org/10.1074/jbc.R115.652750

[100]

Hayashi Y, Shi SH, Esteban JA, et al., 2000, Driving AMPA receptors into synapses by LTP and CaMKII: Requirement for GluR1 and PDZ domain interaction. Science, 287: 2262–2267. https://doi.org/10.1126/science.287.5461.2262

[101]

Mattison HA, Hayashi T, Barria A, 2012, Palmitoylation at two cysteine clusters on the C-terminus of GluN2A and GluN2B differentially control synaptic targeting of NMDA receptors. PLoS One, 7: e49089. https://doi.org/10.1371/journal.pone.0049089 

[102]

Gu Y, Huganir RL, 2016, Identification of the SNARE complex mediating the exocytosis of NMDA receptors. Proc Natl Acadf Sci U S A, 113: 12280–12285. https://doi.org/10.1073/pnas.1614042113

[103]

Ladepeche L, Dupuis JP, Groc L, 2014, Surface trafficking of NMDA receptors: Gathering from a partner to another. Seminars Cell Dev Biol, 27: 3–13. https://doi.org/10.1016/j.semcdb.2013.10.005

[104]

Sudhof TC, Rothman JE, 2009, Membrane fusion: grappling with SNARE and SM proteins. Science, 323: 474–477. https://doi.org/10.1126/science.1161748

[105]

Lan JY, Skeberdis VA, Jover T, et al., 2001, Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci, 4(4): 382–390. https://doi.org/10.1038/86028

[106]

Lan JY, Skeberdis VA, Jover T, et al., 2001, Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking. J Neurosci, 21(16): 6058–6068.

[107]

Lau CG, Takayasu Y, Rodenas-Ruano A, et al., 2010, SNAP- 25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. J Neurosci, 30(1): 242–254. https://doi.org/10.1523/JNEUROSCI.4933-08.2010

[108]

Jurado S, Goswami D, Zhang Y, et al., 2013, LTP requires a unique postsynaptic SNARE fusion machinery. Neuron, 77(3): 542–558. https://doi.org/10.1016/j.neuron.2012.11.029

[109]

Washbourne P, Liu XB, Jones EG, et al., 2004, Cycling of NMDA receptors during trafficking in neurons before synapse formation. J Neurosci, 24(38): 8253–8264. https://doi.org/10.1523/JNEUROSCI.2555-04.2004 

[110]

Suh YH, Terashima A, Petralia RS, et al., 2010, A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci, 13(3): 338–343. https://doi.org/10.1038/nn.2488

[111]

Tovar KR, Westbrook GL, 2002, Mobile NMDA receptors at hippocampal synapses. Neuron, 34(2): 255–264. https://doi.org/10.1016/s0896-6273(02)00658-x

[112]

Groc L, Heine M, Cousins SL, et al., 2006, NMDA receptor surface mobility depends on NR2A-2B subunits. Proc Natl Acad Sci U S A, 103(49): 18769–18774. https://doi.org/10.1073/pnas.0605238103

[113]

Dupuis JP, Ladepeche L, Seth H, et al., 2014, Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses. EMBO J, 33(8): 842–861. https://doi.org/10.1002/embj.201386356

[114]

Ferreira JS, Papouin T, Ladépêche L, et al., 2017, Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses. ELife 6: e25492. https://doi.org/10.7554/eLife.25492

[115]

Sun YJ, Xu YG, Chen XK, et al., 2018, The differences between GluN2A and GluN2B signaling in the brain. J Neuro Res, 96: 1430–1443. https://doi.org/10.1002/jnr.24251

[116]

Kellermayer B, Ferreira JS, Dupuis J, et al., 2018, Differential nanoscale topography and functional role of GluN2-NMDA receptor subtypes at glutamatergic synapses. Neuron, 100(1): 106–119. e107. https://doi.org/10.1016/j.neuron.2018.09.012

[117]

Bard L, Sainlos M, Bouchet D, et al., 2010, Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. Proc Natl Acad Sci U S A, 107(45): 19561–19566. https://doi.org/10.1073/pnas.1002690107

[118]

Chung HJ, Huang YH, Lau LF, et al., 2004, Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J Neurosci, 24: 10248–10259. https://doi.org/10.1523/JNEUROSCI.0546-04.2004

[119]

Chiu AM, Wang J, Fiske MP, et al., 2019, NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content. Cell Rep, 28(2): 332–341 e335. https://doi.org/10.1016/j.celrep.2019.06.030 

[120]

Lesept F, Chevilley A, Jezequel J, et al., 2016, Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors. Cell Death Dis, 7(11): e2466. https://doi.org/10.1038/cddis.2016.279

[121]

Michaluk P, Groc L, Mikasova L, et al., 2009, Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin beta1 signaling. J Neurosci, 29(18): 6007–6012. https://doi.org/10.1523/JNEUROSCI.5346-08.2009

[122]

Mikasova L, Xiong H, Kerkhofs A, et al., 2017, Stress hormone rapidly tunes synaptic NMDA receptor through membrane dynamics and mineralocorticoid signalling. Sci Rep, 7: 8053. https://doi.org/10.1038/s41598-017-08695-3

[123]

Potier M, Georges F, Brayda-Bruno L, et al., 2016, Temporal memory and its enhancement by estradiol requires surface dynamics of hippocampal CA1 N-methyl-D-aspartate receptors. Biol Psychiatry, 79: 735–745. https://doi.org/1016/j.biopsych.2015.07.017

[124]

Roche KW, Standley S, McCallum J, et al., 2001, Molecular determinants of NMDA receptor internalization. Nature Neurosci, 4: 794–802. https://doi.org/1038/90498

[125]

Lavezzari G, McCallum J, Dewey CM, et al., 2004, Subunit-specific regulation of NMDA receptor endocytosis. J Neurosci, 24: 6383–6391. https://doi.org/1523/JNEUROSCI.1890-04.2004

[126]

Blanpied TA, Scott DB, Ehlers MD, 2002, Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron, 36: 435–449. https://doi.org/1016/s0896-6273(02)00979-0

[127]

Prybylowski K, Chang K, Sans N, et al., 2005, The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron, 47: 845–857. https://doi.org/1016/j.neuron.2005.08.016

[128]

Lavezzari G, McCallum J, Lee R, et al., 2003, Differential binding of the AP-2 adaptor complex and PSD-95 to the C-terminus of the NMDA receptor subunit NR2B regulates surface expression. Neuropharmacology, 45: 729–737. https://doi.org/1016/s0028-3908(03)00308-3

[129]

Scott DB, Michailidis I, Mu Y, et al., 2004, Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals. J Neurosci, 24: 7096–7109. https://doi.org/1523/JNEUROSCI.0780-04.2004

[130]

Bliss TV, Lomo T, 1973, Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol, 232: 331–356. https://doi.org/1113/jphysiol.1973.sp010273

[131]

Collingridge GL, Kehl SJ, McLennan H, 1983, The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro. J Physiol, 334: 19–31. https://doi.org/1113/jphysiol.1983.sp014477

[132]

Morris RG, 1989, Synaptic plasticity and learning: Selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci, 9: 3040–3057.

[133]

Morris RG, Anderson E, Lynch GS, et al., 1986, Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature, 319: 774–776. https://doi.org/1038/319774a0

[134]

Norris CM, Foster TC, 1999, MK-801 improves retention in aged rats: Implications for altered neural plasticity in age-related memory deficits. Neurobiol Learn Mem, 71: 194–206. https://doi.org/1006/nlme.1998.3864

[135]

Villarreal DM, Do V, Haddad E, et al., NMDA receptor antagonists sustain LTP and spatial memory: Active processes mediate LTP decay. Nat Neurosci, 5: 48–52. https://doi.org/1038/nn776

[136]

Josselyn SA, Nguyen PV, 2005, CREB, synapses and memory disorders: past progress and future challenges. Curr Drug Targets CNS Neurol Disord, 4: 481–497. https://doi.org/2174/156800705774322058

[137]

Malinow R, Malenka RC, 2002, AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci, 25: 103–126. https://doi.org/1146/annurev.neuro.25.112701.142758 

[138]

Citri A, Malenka RC, 2008, Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology, 33: 18–41. https://doi.org/1038/sj.npp.1301559

[139]

Malenka RC, 2003, Synaptic plasticity and AMPA receptor trafficking. Ann N Y Acad Sci, 1003: 1–11. https://doi.org/1196/annals.1300.001

[140]

Malenka RC, Bear MF, 2004, LTP and LTD: an embarrassment of riches. Neuron, 44: 5–21. https://doi.org/1016/j.neuron.2004.09.012

[141]

Strack S, Colbran RJ, 1998, Autophosphorylation-dependent targeting of calcium/calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl- D-aspartate receptor. J Biol Chem, 273: 20689–20692. https://doi.org/1074/jbc.273.33.20689

[142]

Barria A, Malinow R, 2005, NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron, 48: 289–301. https://doi.org/1016/j.neuron.2005.08.034 

[143]

Lu HC, Gonzalez E, Crair MC, 2001, Barrel cortex critical period plasticity is independent of changes in NMDA receptor subunit composition. Neuron, 32: 619–634. https://doi.org/1016/s0896-6273(01)00501-3

[144]

Zhao MG, Toyoda H, Lee YS, et al., 2005, Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron, 47: 859-872. https://doi.org/1016/j.neuron.2005.08.014

[145]

Akashi K, Kakizaki T, Kamiya H, et al., 2009, NMDA receptor GluN2B (GluR epsilon 2/NR2B) subunit is crucial for channel function, postsynaptic macromolecular organization, and actin cytoskeleton at hippocampal CA3 synapses. J Neurosci, 29: 10869–10882. https://doi.org/1523/JNEUROSCI.5531-08.2009

[146]

Brigman JL, Wright T, Talani G, et al., 2010, Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci, 30: 4590–4600. https://doi.org/1523/JNEUROSCI.0640-10.2010

[147]

Von Engelhardt, J., Doganci B, Jensen V, et al., 2008, Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron, 60: 846–860. https://doi.org/1016/j.neuron.2008.09.039(2008) 

[148]

Tang YP, Shimizu E, Dube GR, et al., 1999, Genetic enhancement of learning and memory in mice. Nature, 401: 63–69. https://doi.org/1038/43432

[149]

Zhou Y, Takahashi E, Li W, et al., 2007, Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. J Neurosci, 27: 13843–13853. https://doi.org/1523/JNEUROSCI.4486-07.2007

[150]

Berberich S, Punnakkal P, Jensen V, et al., Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. J Neurosci, 25: 6907–6910. https://doi.org/1523/JNEUROSCI.1905-05.2005

[151]

Weitlauf C, Honse Y, Auberson YP, et al., 2005, Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation. J Neurosci, 25: 8386–8390. https://doi.org/1523/JNEUROSCI.2388-05.2005

[152]

Cui Z, Feng R, Jacobs S, et al., Increased NR2A: NR2B ratio compresses long-term depression range and constrains long-term memory. Sci Rep, 3: 1036. https://doi.org/1038/srep01036

[153]

Hawasli AH, Benavides DR, Nguyen C, et al., 2007,  Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci, 10: 880–886. https://doi.org/1038/nn1914

[154]

Liu L, Wong TP, Pozza MF, et al., 2004, Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science, 304: 1021–1024. https://doi.org/1126/science.1096615

[155]

Li R, Huang FS, Abbas AK, et al., 2007, Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci, 8: 55. https://doi.org/1186/1471-2202-8-55

[156]

Sakimura K, Kutsuwada T, Ito I, et al., 1995, Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature, 373: 151–155. https://doi.org/1038/373151a0

[157]

Foster KA, McLaughlin N, Edbauer D, et al., 2010, Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. J Neurosci, 30: 2676–2685. https://doi.org/1523/JNEUROSCI.4022-09.2010

[158]

Delaney AJ, Sedlak PL, Autuori E, et al., 2013, Synaptic NMDA receptors in basolateral amygdala principal neurons are triheteromeric proteins: Physiological role of GluN2B subunits. J Neurophysiol, 109: 1391–1402. https://doi.org/1152/jn.00176.2012

[159]

Morishita W, Lu W, Smith GB, et al., 2007, Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression. Neuropharmacology, 52: 71–76. https://doi.org/1016/j.neuropharm.2006.07.005

[160]

Hendricson AW, Miao CL, Lippmann MJ, et al., 2002, Ifenprodil and ethanol enhance NMDA receptor-dependent long-term depression. J Pharmacol Exp Ther, 301: 938-944. https://doi.org/1124/jpet.301.3.938

[161]

Gardoni F, Mauceri D, Malinverno M, et al., 2009, Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression. J Neurosci, 29: 669–677. https://doi.org/1523/JNEUROSCI.3921-08.2009 

[162]

Wang D, Cui Z, Zeng Q, et al., 2009, Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats. PLoS One, 4: e7486. https://doi.org/1371/journal.pone.0007486 

[163]

Bartlett TE, Bannister NJ, Collett VJ, et al., 2007, Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology, 52: 60–70. https://doi.org/1016/j.neuropharm.2006.07.013

[164]

Ge Y, Dong Z, Bagot RC, et al., 2010, Hippocampal long-term depression is required for the consolidation of spatial memory. Proc Natl Acad Sci U S A, 107: 16697–16702. https://doi.org/1073/pnas.1008200107

[165]

Longordo F, Kopp C, Mishina M, et al., 2009, NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss. J Neurosci., 29: 9026–9041. https://doi.org/1523/JNEUROSCI.1215-09.2009 

[166]

Kalia LV, Kalia SK, Salter MW, 2008, NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol, 7: 742–755. https://doi.org/1016/S1474-4422(08)70165-0

[167]

Berman RM, Cappiello A, Anand A, et al., 2000, Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 47: 351–354. https://doi.org/1016/s0006-3223(99)00230-9

[168]

Murrough JW, Perez AM, Pillemer S, et al., 2013, Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry, 74: 250–256. https://doi.org/1016/j.biopsych.2012.06.022

[169]

Preskorn S, Macaluso M, Mehra DO, et al., 2015, Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatric Pract, 21: 140–149. https://doi.org/1097/01.pra.0000462606.17725.93

[170]

Jiang J, Jiang H, 2015, Efficacy and adverse effects of memantine treatment for Alzheimer’s disease from randomized controlled trials. Neurol Sci, 36: 1633–1641. https://doi.org/1007/s10072-015-2221-2

[171]

Knapp M, King D, Romeo R, et al., 2017, Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer’s disease (the DOMINO-AD trial). Int J Geriatr Psychiatry, 32: 1205–1216. https://doi.org/1002/gps.4583 

[172]

O’Collins VE, Macleod MR, Donnan GA, et al., 2006, 1,026 experimental treatments in acute stroke. Ann Neurol, 59: 467–477. https://doi.org/1002/ana.20741

[173]

Feng B, Morley RM, Jane DE, et al., 2005, The effect of competitive antagonist chain length on NMDA receptor subunit selectivity. Neuropharmacology, 48: 354–359. https://doi.org/1016/j.neuropharm.2004.11.004 

[174]

Auberson YP, Allgeier H, Bischoff S, et al., 2002, 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition.  Bioorg Med Chem Lett, 12: 1099–1102. https://doi.org/1016/s0960-894x(02)00074-4

[175]

Hood WF, Sun ET, Compton RP, et al., 1989, 1-Aminocyclobutane-1-carboxylate (ACBC): A specific antagonist of the N-methyl-D-aspartate receptor coupled glycine receptor. Eur J Pharmacol, 161: 281–282. https://doi.org/1016/0014-2999(89)90861-3

[176]

Kemp JA, Foster AC, Leeson PD, et al., 1988, 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A, 85: 6547–6550. https://doi.org/1073/pnas.85.17.6547

[177]

Davies J, Watkins JC, 1972, Is 1-hydroxy-3- aminopyrrolidone-2 (HA-966) a selective excitatory amino-acid antagonist? Nat New Biol, 238: 61–63. https://doi.org/1038/newbio238061a0

[178]

Priestley T, Laughton P, Macaulay AJ, et al., 1996, Electrophysiological characterisation of the antagonist properties of two novel NMDA receptor glycine site antagonists, L-695,902 and L-701,324. Neuropharmacology, 35: 1573–1581. https://doi.org/1016/s0028-3908(96)00141-4

[179]

Anis N, Sherby S, Goodnow R Jr., et al., 1990, Structure-activity relationships of philanthotoxin analogs and polyamines on N-methyl-D-aspartate and nicotinic acetylcholine receptors. J Pharmacol Exp Ther, 254: 764–773.

[180]

Lodge D, Johnson KM, 1990, Noncompetitive excitatory amino acid receptor antagonists. Trends Pharmacol Sci, 11: 81–86. https://doi.org/1016/0165-6147(90)90323-z

[181]

Wong EH, Kemp JA, Priestley T, et al., 1986, The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A, 83: 7104–7108. https://doi.org/1073/pnas.83.18.7104

[182]

Carter C, Rivy JP, Scatton B, 1989, Ifenprodil and SL 82.0715 are antagonists at the polyamine site of the N-methyl-D-aspartate (NMDA) receptor. Eur J Pharmacol, 164: 611–612. https://doi.org/1016/0014-2999(89)90275-6

[183]

Karakas E, Simorowski N, Furukawa H, 2011, Subunit arrangement and phenylethanolamine binding in GluN1/ GluN2B NMDA receptors. Nature, 475: 249–253. https://doi.org/1038/nature10180 

[184]

Chenard BL, Bordner J, Butler TW, et al., 1995, (1S,2S)-1- (4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- 1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem, 38: 3138–3145. https://doi.org/1021/jm00016a017

[185]

Fischer G, et al., 1997, Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther, 283: 1285–1292.

[186]

Bettini E, Sava A, Griffante C, et al., 2010, Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors. J Pharmacol Exp Ther, 335: 636–644. https://doi.org/1124/jpet.110.172544

[187]

Hansen KB, Ogden KK, Traynelis SF, 2012, Subunit-selective allosteric inhibition of glycine binding to NMDA receptors. J Neurosci, 32: 6197–6208. https://doi.org/1523/JNEUROSCI.5757-11.2012

[188]

Edman S, McKay S, MacDonald LJ, et al., 2012, TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner. Neuropharmacology, 63: 441–449. https://doi.org/1016/j.neuropharm.2012.04.

[189]

Mosley CA, Acker TM, Hansen KB, et al., 2010, Quinazolin- 4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists. J Med Chem, 53: 5476–5490. https://doi.org/1021/jm100027p

[190]

Hansen KB, Traynelis SF, 2011, Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors. J Neurosci, 31: 3650–3661. https://doi.org/1523/JNEUROSCI.5565-10.2011

[191]

Costa BM, Irvine MW, Fang G, et al., 2010, A novel family of negative and positive allosteric modulators of NMDA receptors. J Pharmacol Exp Ther, 335: 614–621. https://doi.org/1124/jpet.110.174144

[192]

Costa BM, Irvine MW, Fang G, et al., 2012, Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid. Neuropharmacology, 62: 1730–1736. https://doi.org/1016/j.neuropharm.2011.11.019 

[193]

Kloda A, Clements JD, Lewis RJ, et al., 2004, Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors. Mol Pharmacol, 65: 1386–1396. https://doi.org/1124/mol.65.6.1386

[194]

Williams K, 1994, Subunit-specific potentiation of recombinant N-methyl-D-aspartate receptors by histamine. Mol Pharmacol, 46: 531–541.

[195]

Williams K, Zappia AM, Pritchett DB, et al., 1994, Sensitivity of the N-methyl-D-aspartate receptor to polyamines is controlled by NR2 subunits. Mol Pharmacol, 45: 803–809.

[196]

Sedlacek M, Korínek M, Petrovic M, et al., 2008, Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission. Physiol Res, 57(Suppl 3): S49–S57. https://doi.org/33549/physiolres.931600 

[197]

Paoletti P, Neyton J, Ascher P, 1995, Glycine-independent and subunit-specific potentiation of NMDA responses by extracellular Mg2+. Neuron, 15: 1109–1120. https://doi.org/1016/0896-6273(95)90099-3

[198]

Malayev A, Gibbs TT, Farb DH, 2002, Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. Br J Pharmacol, 135: 901–909. https://doi.org/1038/sj.bjp.0704543

[199]

Petrovic M, Sedlacek M, Cais O, et al., 2009, Pregnenolone sulfate modulation of N-methyl-D-aspartate receptors is phosphorylation dependent. Neuroscience, 160: 616–628. https://doi.org/1016/j.neuroscience.2009.02.052

[200]

Horak M, Vlcek K, Petrovic M, et al., 2004, Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors. J Neurosci, 24: 10318–10325. https://doi.org/1523/JNEUROSCI.2099-04.2004

[201]

Bowlby MR, 1993, Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons. Mol Pharmacol, 43: 813–819.

[202]

Wong M, Moss RL, 1994, Patch-clamp analysis of direct steroidal modulation of glutamate receptor-channels. J Neuroendocrinol, 6: 347–355. https://doi.org/1111/j.1365-2826.1994.tb00592.x 

[203]

Jang MK, Mierke DF, Russek SJ, et al., 2004, A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity. Proc Natl Acad Sci U S A, 101: 8198–8203. https://doi.org/1073/pnas.0401838101

[204]

Monaghan DT, Irvine MW, Costa BM, et al., 2012, Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. Neurochem Int, 61: 581–592. https://doi.org/1016/j.neuint.2012.01.004

[205]

Sapkota K, Irvine MW, Fang G, et al., 2017, Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives. Neuropharmacology, 125: 64–79. https://doi.org/1016/j.neuropharm.2017.07.007

[206]

Chopra DA, Sapkota K, Irvine MW, et al., 2017, A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors. Sci Rep, 7: 6933. https://doi.org/1038/s41598-017-07292-8

[207]

Irvine MW, Costa BM, Dlaboga D, et al., 2012, Piperazine- 2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors. J Med Chem, 55: 327–341. https://doi.org/1021/jm201230z

[208]

Mullasseril P, Hansen KB, Vance KM, et al., 2010, A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors. Nat Commun, 1: 90. https://doi.org/1038/ncomms1085

[209]

Zhang X, Feng ZJ, Chergui K, 2014, Allosteric modulation of GluN2C/GluN2D-containing NMDA receptors bidirectionally modulates dopamine release: implication for Parkinson’s disease. Br J Pharmacol, 171: 3938–3945. https://doi.org/1111/bph.12758

[210]

Wang TM, Brown BM, Deng L, et al., 2017, A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain. Neuropharmacology, 121: 204–218. https://doi.org/1016/j.neuropharm.2017.04.041

[211]

Kessels HW, Nabavi S, Malinow R, 2013, Metabotropic NMDA receptor function is required for beta-amyloid-induced synaptic depression. Proc Natl Acad Sci U S A, 110: 4033–4038. https://doi.org/1073/pnas.1219605110

[212]

Ronicke R, Mikhaylova M, Rönicke S, et al., 2011, Early neuronal dysfunction by amyloid beta oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiol Aging, 32: 2219–2228. https://doi.org/1016/j.neurobiolaging.2010.01.011

[213]

Li S, Jin M, Koeglsperger T, et al., 2011, Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci, 31: 6627–6638. https://doi.org/1523/JNEUROSCI.0203-11.2011 

[214]

Hu NW, Klyubin I, Anwyl R, et al., 2009, GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo. Proc Natl Acad Sci U S A, 106: 20504–20509. https://doi.org/1073/pnas.0908083106

[215]

Li S, Hong S, Shepardson NE, et al., 2009, Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron, 62: 788–801. https://doi.org/1016/j.neuron.2009.05.012

[216]

Ittner LM, Ke YD, Delerue F, et al., 2010, Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell, 142: 387–397. https://doi.org/1016/j.cell.2010.06.036

[217]

Bordji K, Becerril-Ortega J, Nicole O, et al., 2010, Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ss production. J Neurosci, 30: 15927–15942. https://doi.org/1523/JNEUROSCI.3021-10.2010

[218]

Lai TW, Shyu WC, Wang YT, 2011, Stroke intervention pathways: NMDA receptors and beyond. Trends Mol Med, 17: 266–275. https://doi.org/1016/j.molmed.2010.12.008

[219]

Dunah AW, Wang Y, Yasuda RP, et al., 2000, Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson’s disease. Mol Pharmacol, 57: 342–352.

[220]

Gardoni F, Picconi B, Ghiglieri V, et al., 2006, A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. J Neurosci, 26: 2914–2922. https://doi.org/1523/JNEUROSCI.5326-05.2006

[221]

Mony L, Kew JN, Gunthorpe MJ, et al., 2009, Allosteric modulators of NR2B-containing NMDA receptors: Molecular mechanisms and therapeutic potential. Br J Pharmacol, 157: 1301–1317. https://doi.org/1111/j.1476-5381.2009.00304.x

[222]

Sgambato-Faure V, Cenci MA, 2012, Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson’s disease. Prog Neurobiol, 96: 69–86. https://doi.org/1016/j.pneurobio.2011.10.005

[223]

Gardoni F, Sgobio C, Pendolino V, et al., 2012, Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias. Neurobiol Aging, 33: 2138–2144. https://doi.org/1016/j.neurobiolaging.2011.06.019

[224]

Nakazawa K, Sapkota K, 2020, The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther, 205: 107426. https://doi.org/1016/j.pharmthera.2019.107426

[225]

Howes OD, Kapur S, 2009, The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull, 35: 549–562. https://doi.org/1093/schbul/sbp006

[226]

Moghaddam B, Javitt D, 2012, From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology, 37: 4–15. https://doi.org/1038/npp.2011.181

[227]

Mohn AR, Gainetdinov RR, Caron MG, et al., 1999, Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell, 98: 427–436. https://doi.org/1016/s0092-8674(00)81972-8

[228]

Nakao K, Jeevakumar V, Jiang SZ, et al., 2019, Schizophrenia-like dopamine release abnormalities in a mouse model of NMDA receptor hypofunction. Schizophr Bull, 45: 138–147. https://doi.org/1093/schbul/sby003

[229]

Coyle JT, Tsai G, Goff D, 2003, Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci, 1003: 318–327. https://doi.org/1196/annals.1300.020

[230]

Javitt DC, Zukin SR, 1991, Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry, 148: 1301–1308. https://doi.org/1176/ajp.148.10.1301 

[231]

Krystal JH, Karper LP, Seibyl JP, et al., 1994, Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry, 51: 199–214. https://doi.org/1001/archpsyc.1994.03950030035004

[232]

Koek W, Woods JH, Winger GD, 1988, MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther, 245: 969–974.

[233]

Kovacic P, Somanathan R, 2010, Clinical physiology and mechanism of dizocilpine (MK-801): Electron transfer, radicals, redox metabolites and bioactivity. Oxid Med Cell Longev, 3: 13–22. https://doi.org/4161/oxim.3.1.10028

[234]

Dalmau J, Lancaster E, Martinez-Hernandez E, et al., 2011, Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol, 10: 63–74. https://doi.org/1016/S1474-4422(10)70253-2 

[235]

1993, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell, 72: 971–983. https://doi.org/1016/0092-8674(93)90585-e

[236]

Fan MM, Raymond LA, 2007, N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol, 81: 272–293. https://doi.org/1016/j.pneurobio.2006.11.003

[237]

Milnerwood AJ, Gladding CM, Pouladi MA, et al., 2010, Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington’s disease mice. Neuron, 65: 178–190. https://doi.org/1016/j.neuron.2010.01.008

[238]

Okamoto S, Pouladi MA, Talantova M, et al., 2009, Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant  huntingtin. Nat Med, 15: 1407–1413. https://doi.org/1038/nm.2056

[239]

GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, 2016, Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the global burden of disease study 2015. Lancet, 388: 1545–1602. https://doi.org/1016/S0140-6736(16)31678-6 

[240]

Tiller JW, 2013, Depression and anxiety. Med J Aust, 199: S28–S31. https://doi.org/5694/mja12.10628

[241]

Diefenbach GJ, McCarthy-Larzelere ME, Williamson DA, et al., 2001, Anxiety, depression, and the content of worries. Depression Anxiety, 14: 247–250. https://doi.org/1002/da.1075

[242]

Feifel D, 2016, Breaking sad: Unleashing the breakthrough potential of Ketamine’s rapid antidepressant effects. Drug Dev Res, 77: 489–494. https://doi.org/1002/ddr.21347 

[243]

Fukumoto K, Toki H, Iijima M, et al., 2017, Antidepressant potential of (R)-ketamine in rodent models: Comparison with (S)-ketamine. J Pharmacol Exp Ther, 361: 9–16. https://doi.org/1124/jpet.116.239228

[244]

Ionescu DF, Fu DJ, Qiu X, et al., 2021, Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol, 24: 22–31. https://doi.org/1093/ijnp/pyaa068

[245]

Pittenger C, Sanacora G, Krystal JH, 2007, The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disord Drug Targets, 6: 101–115. https://doi.org/2174/187152707780363267

[246]

Feyissa AM, Chandran A, Stockmeier CA, et al., 2009, Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry, 33: 70–75. https://doi.org/1016/j.pnpbp.2008.10.005

[247]

Karolewicz B, Stockmeier CA, Ordway GA, 2005, Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. Neuropsychopharmacology, 30: 1557–1567. https://doi.org/1038/sj.npp.1300781 

[248]

Karolewicz B, Stockmeier CA, Ordway GA, 2009, Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int J Neuropsychopharmacol, 12: 143–153. https://doi.org/1017/S1461145708008985 

[249]

Jiang A, Su P, Li S, et al., 2021, Disrupting the alpha7nAChR-NR2A protein complex exerts antidepressant-like effects. Mol Brain, 14: 107. https://doi.org/1186/s13041-021-00817-3

[250]

Zanos P, Moaddel R, Morris PJ, et al., 2016, NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533: 481–486. https://doi.org/1038/nature17998

[251]

Bullock R, Zauner A, Woodward JJ, et al., 1998, Factors affecting excitatory amino acid release following severe human head injury. J Neurosurg, 89: 507–518. https://doi.org/3171/jns.1998.89.4.0507

[252]

Simon RP, Swan JH, Griffiths T, et al., 1984, Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science, 226: 850–852. https://doi.org/1126/science.6093256

[253]

Chen MH, Bullock R, Graham DI, et al., 1991, Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist. J Neurosurg, 74: 944–950. https://doi.org/3171/jns.1991.74.6.0944

[254]

Margaill I, Parmentier S, Callebert J, et al., 1996, Short therapeutic window for MK-801 in transient focal cerebral ischemia in normotensive rats. J Cerebral Blood Flow Metab, 16: 107–113. https://doi.org/1097/00004647-199601000-00013

[255]

Liu Y, Wong TP, Aarts M, et al., 2007, NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci, 27: 2846–2857. https://doi.org/1523/JNEUROSCI.0116-07.2007 

[256]

Chen M, Lu TJ, Chen XJ, et al., 2008, Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke, 39: 3042–3048. https://doi.org/1161/STROKEAHA.108.521898

[257]

Yang Y, Li Q, Yang T, et al., 2003, Reduced brain infarct volume and improved neurological outcome by inhibition of the NR2B subunit of NMDA receptors by using CP101,606-27 alone and in combination with rt-PA in a thromboembolic stroke model in rats. J Neurosurg, 98: 397–403. https://doi.org/3171/jns.2003.98.2.0397

[258]

Aarts M, Liu Y, Liu L, et al., 2002, Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science, 298: 846–850. https://doi.org/1126/science.1072873

[259]

Cook DJ, Teves L, Tymianski M, 2012, A translational  paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Sci Transl Med, 4: 154ra133. https://doi.org/1126/scitranslmed.3003824

[260]

Hill MD, Martin RH, Mikulis D, et al., 2012, Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol, 11: 942–950. https://doi.org/1016/S1474-4422(12)70225-9

[261]

Beauchamp K, Mutlak H, Smith WR, et al., 2008, Pharmacology of traumatic brain injury: Where is the “golden bullet”? Mol Med, 14: 731–740. https://doi.org/2119/2008-00050.Beauchamp

[262]

Biegon A, Fry PA, Paden CM, et al., 2004, Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci U S A, 101: 5117–5122. https://doi.org/1073/pnas.0305741101

[263]

Carter DS, Deshpande LS, Rafiq A, et al., 2011, Characterization of spontaneous recurrent epileptiform discharges in hippocampal-entorhinal cortical slices prepared from chronic epileptic animals. Seizure, 20: 218–224. https://doi.org/1016/j.seizure.2010.11.022

[264]

Meldrum BS, 1993, Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol, 3: 405–412. https://doi.org/1111/j.1750-3639.1993.tb00768.x

[265]

Jensen PJ, Millan N, Mack KJ, 1997, Cortical NMDAR-1 gene expression is rapidly upregulated after seizure. Brain Res Mol Brain Res, 44: 157–162. https://doi.org/1016/s0169-328x(96)00262-8

[266]

Kikuchi S, Iwasa H, Sato T, 2000, Lasting changes in NMDAR1 mRNA level in various regions of cerebral cortex in epileptogenesis of amygdaloid-kindled rat. Psychiatry Clin Neurosci, 54: 573–577. https://doi.org/1046/j.1440-1819.2000.00755.x

[267]

Gerfin-Moser A, Grogg F, Rietschin L, et al., 1995, Alterations in glutamate but not GABAA receptor subunit expression as a consequence of epileptiform activity in vitro. Neuroscience, 67: 849-865. https://doi.org/1016/0306-4522(95)00130-b

[268]

Mathern GW, Pretorius JK, Leite JP, et al., 1998, Hippocampal AMPA and NMDA mRNA levels and subunit immunoreactivity in human temporal lobe epilepsy patients and a rodent model of chronic mesial limbic epilepsy. Epilepsy Res, 32: 154–171. https://doi.org/1016/s0920-1211(98)00048-5 

[269]

Lason W, Turchan J, Przewłocki R, et al., 1997, Effects of pilocarpine and kainate-induced seizures on N-methyl-D-aspartate receptor gene expression in the rat hippocampus. Neuroscience, 78: 997–1004. https://doi.org/1016/s0306-4522(96)00635-5

[270]

Hosain S, Nagarajan L, Carson D, et al., 1997, Felbamate for refractory infantile spasms. J Child Neurol, 12: 466–468. https://doi.org/1177/088307389701200711

[271]

Zupanc ML, Werner RR, Schwabe MS, et al., 2010, Efficacy of felbamate in the treatment of intractable pediatric epilepsy. Pediatr Neurol, 42: 396–403. https://doi.org/1016/j.pediatrneurol.2010.02.013

[272]

McCabe RT, Wasterlain CG, Kucharczyk N, et al., 1993, Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors. J Pharmacol Exp Ther, 264: 1248–1252.

[273]

White HS, Harmsworth WL, Sofia RD, et al., 1995, Felbamate modulates the strychnine-insensitive glycine receptor. Epilepsy Res, 20: 41–48. https://doi.org/1016/0920-1211(94)00066-6

[274]

Rho JM, Donevan SD, Rogawski MA, 1994, Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-D-aspartate and gamma-aminobutyric acidA receptors. Ann Neurol, 35: 229–234. https://doi.org/1002/ana.410350216

[275]

Singh L, Oles RJ, Vass CA, et al., 1991, A slow intravenous infusion of N-methyl-DL-aspartate as a seizure model in the mouse. J Neurosci Methods, 37: 227–232. https://doi.org/1016/0165-0270(91)90028-x

[276]

Balosso S, Maroso M, Sanchez-Alavez M, et al., 2008, A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain, 131: 3256–3265. https://doi.org/1093/brain/awn271

[277]

Yen W, Williamson J, Bertram EH, et al., 2004, A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus. Epilepsy Res, 59: 43–50. https://doi.org/1016/j.eplepsyres.2004.03.004

[278]

Kleinrok Z, Turski WA, Czuczwar SJ, 1995, Excitatory amino acid antagonists and the anticonvulsive activity of conventional antiepileptic drugs. Polish J Pharmacol, 47: 247–252.

[279]

Brackett RL, Pouw B, Blyden JF, et al., 2000, Prevention of cocaine-induced convulsions and lethality in mice: Effectiveness of targeting different sites on the NMDA receptor complex. Neuropharmacology, 39: 407–418. https://doi.org/1016/s0028-3908(99)00151-3

[280]

Vataev SI, Zhabko EP, Lukomskaia N, et al., 2009, Effects of memantine on convulsive reactions and sleep-waking cycle  in Krushinskii-Molodkina strain rats with the inherited predisposition to audiogenic convulsions. Ross Fiziol Zh Im I M Sechenova, 95: 802–812.

[281]

Frey HH, Voits M, 1991, Effect of psychotropic agents on a model of absence epilepsy in rats. Neuropharmacology, 30: 651–656. https://doi.org/1016/0028-3908(91)90086-q

[282]

Czuczwar SJ, Turski WA, Kleinrok Z, 1996, Interactions of excitatory amino acid antagonists with conventional antiepileptic drugs. Metab Brain Dis, 11: 143–152. https://doi.org/1007/BF02069501 

[283]

Wu LJ, Zhuo M, 2009, Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics, 6: 693–702. https://doi.org/1016/j.nurt.2009.07.008

[284]

Woolf CJ, Salter MW, Neuronal plasticity: increasing the gain in pain. Science, 288: 1765–1769. https://doi.org/1126/science.288.5472.1765

[285]

Isaev D, Gerber G, Park SK, et al., 2000, Facilitation of NMDA-induced currents and Ca2+ transients in the rat substantia gelatinosa neurons after ligation of L5-L6 spinal nerves. Neuroreport, 11: 4055–4061. https://doi.org/1097/00001756-200012180-00030

[286]

Ultenius C, Linderoth B, Meyerson BA, et al., 2006, Spinal NMDA receptor phosphorylation correlates with the presence of neuropathic signs following peripheral nerve injury in the rat. Neurosci Lett, 399: 85–90. https://doi.org/1016/j.neulet.2006.01.018

[287]

Gao X, Kim HK, Chung JM, et al., 2005, Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain, 116: 62–72. https://doi.org/1016/j.pain.2005.03.045

[288]

Suzuki R, Matthews EA, Dickenson AH, 2001, Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain, 91: 101–109. https://doi.org/1016/s0304-3959(00)00423-1

[289]

Iwata H, Takasusuki T, Yamaguchi S, et al., 2007, NMDA receptor 2B subunit-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-injured neuropathic mice. Brain Res, 1135: 92–101. https://doi.org/1016/j.brainres.2006.12.014

[290]

Correll GE, Maleki J, Gracely EJ, et al., 2004, Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med, 5: 263–275. https://doi.org/1111/j.1526-4637.2004.04043.x.

[291]

Kiefer RT, Rohr P, Ploppa A, et al., 2008, Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: An open-label phase II study. Pain Med, 9: 1173–1201. https://doi.org/1111/j.1526-4637.2007.00402.x

[292]

Duale C, Sibaud F, Guastella V, et al., 2009, Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain, 13: 497–505. https://doi.org/1016/j.ejpain.2008.06.013

[293]

Pud D, Eisenberg E, Spitzer A, et al., 1998, The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: A double blind, randomized, placebo controlled trial. Pain, 75: 349–354. https://doi.org/1016/s0304-3959(98)00014-1

[294]

Fukui S, Komoda Y, Nosaka S, 2001, Clinical application of amantadine, an NMDA antagonist, for neuropathic pain. J Anesth, 15: 179–181. https://doi.org/1007/s005400170025

[295]

Lancaster CL, Teeters JB, Gros DF, et al., 2016, Posttraumatic stress disorder: Overview of evidence-based assessment and treatment. J Clin Med, 5: 105. https://doi.org/3390/jcm5110105

[296]

Gates MA, Holowka DW, Vasterling JJ, et al., 2012, Posttraumatic stress disorder in veterans and military personnel: Epidemiology, screening, and case recognition. Psychol Serv, 9: 361–382. https://doi.org/1037/a0027649

[297]

Yuan K, Gong YM, Liu L, et al., Prevalence of posttraumatic stress disorder after infectious disease pandemics in the twenty-first century, including COVID-19: A meta-analysis and systematic review. Mol Psychiatry, 26: 4982–4998. https://doi.org/1038/s41380-021-01036-x

[298]

Sofuoglu M, Rosenheck R, Petrakis I, 2014, Pharmacological treatment of comorbid PTSD and substance use disorder: Recent progress. Addict Behav, 39: 428–433. https://doi.org/1016/j.addbeh.2013.08.014

[299]

Bestha D, Soliman L, Blankenship K, et al., 2018, The walking wounded: Emerging treatments for PTSD. Curr Psychiatry Rep, 20: 94. https://doi.org/1007/s11920-018-0941-8

[300]

Krystal JH, Abdallah CG, Averill LA, et al., 2017, Synaptic loss and the pathophysiology of PTSD: Implications for ketamine as a prototype novel therapeutic. Curr Psychiatry Rep, 19: 74. https://doi.org/1007/s11920-017-0829-z

[301]

Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: A randomized clinical trial. JAMA Psychiatry, 71: 681–688. https://doi.org/1001/jamapsychiatry.2014.62

[302]

McGhee LL, Maani CV, Garza TH, et al., 2008, The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma, 64: S195–8; discussion S197–8. https://doi.org/1097/TA.0b013e318160ba1d

[303]

Zhang LM, Zhou WW, Ji YJ, et al., 2015, Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder. Psychopharmacology, 232: 663–672. https://doi.org/1007/s00213-014-3697-9

[304]

Zimmerman JM, Maren S, 2010, NMDA receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian fear conditioning in rats. Eur J Neurosci, 31: 1664–1670. https://doi.org/1111/j.1460-9568.2010.07223.x

[305]

Liu JL, Li M, Dang XR, et al., 2009, A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a Pavlovian model. PLoS One, 4: e7548. https://doi.org/1371/journal.pone.0007548

[306]

Fry AE, Fawcett KA, Zelnik N, et al., 2018, De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain, 141: 698–712. https://doi.org/1093/brain/awx358

[307]

Yuan H, Low CM, Moody OA, et al., 2015, Ionotropic GABA and glutamate receptor mutations and human neurologic diseases. Mol Pharmacol, 88: 203–217. https://doi.org/1124/mol.115.097998

[308]

Hamdan FF, Gauthier J, Araki Y, et al., 2011, Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet, 88: 306–316. https://doi.org/1016/j.ajhg.2011.02.001

[309]

Lemke JR, Geider K, Helbig KL, et al., 2016, Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology, 86: 2171–2178. https://doi.org/1212/WNL.0000000000002740

[310]

Chen W, Shieh C, Swanger SA, et al., 2017, GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function. J Hum Genet, 62: 589–597. https://doi.org/1038/jhg.2017.19

[311]

Xu XX, Luo JH, 2018, Mutations of N-methyl-D-aspartate receptor subunits in epilepsy. Neurosci Bull, 34: 549–565. https://doi.org/1007/s12264-017-0191-5

[312]

Ohba C, Shiina M, Tohyama J, et al., 2015, GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. Epilepsia, 56: 841–848. https://doi.org/1111/epi.12987

[313]

Pierson TM, Yuan H, Marsh ED, et al., 2014, GRIN2A mutation and early-onset epileptic encephalopathy: Personalized therapy with memantine. Ann Clin Transl Neurol, 1: 190-198. https://doi.org/1002/acn3.39

[314]

Carvill GL, Regan BM, Yendle SC, et al., 2013, GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet, 45: 1073–1076. https://doi.org/1038/ng.2727

[315]

Lemke JR, Lal D, Reinthaler EM, et al., 2013, Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet, 45: 1067–1072. https://doi.org/1038/ng.2728

[316]

Lesca G, Rudolf G, Bruneau N, et al., 2013, GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet, 45: 1061–1066. https://doi.org/1038/ng.2726 

[317]

Xu XX, Liu XR, Fan CY, et al., 2018, Functional investigation of a GRIN2A variant associated with rolandic epilepsy. Neurosci Bull, 34: 237–246. https://doi.org/1007/s12264-017-0182-6

[318]

Yuan H, Tankovic A, Burger PB, et al., 2014, Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun, 5: 3251. https://doi.org/1038/ncomms4251

[319]

Chen W, et al., 2017, Functional evaluation of a de novo GRIN2A mutation identified in a patient with profound global developmental delay and refractory epilepsy. Mol Pharmacol, 91: 317–330. https://doi.org/1124/mol.116.106781

[320]

Endele S, Rosenberger G, Geider K, et al., 2010, Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet, 42: 1021–1026. https://doi.org/1038/ng.677

[321]

Hansen KB, Yi F, Perszyk RE, et al., 2018, Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol, 150: 1081–1105. https://doi.org/1085/jgp.201812032

[322]

Wollmuth LP, Kuner T, Sakmann B, 1998, Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the voltage-dependent block by extracellular Mg2+. J Physiol, 506(Pt 1): 13–32. https://doi.org/1111/j.1469-7793.1998.013bx.x

[323]

Mayer ML, 2006, Glutamate receptors at atomic resolution. Nature, 440: 456–462. https://doi.org/1038/nature04709

[324]

Gao K, Tankovic A, Zhang Y, et al., 2017, A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia. PLoS One, 12: e0170818. https://doi.org/1371/journal.pone.0170818

[325]

Swanger SA, Chen W, Wells G, et al., 2016, Mechanistic insight into nmda receptor dysregulation by rare variants in the GluN2A and GluN2B agonist binding domains. Am J Hum Genet, 99: 1261–1280. https://doi.org/1016/j.ajhg.2016.10.002

[326]

Vieira MM, Nguyen TA, Wu K, et al., 2020, An epilepsy-associated GRIN2A rare variant disrupts CaMKIIalpha phosphorylation of GluN2A and NMDA receptor trafficking. Cell Rep, 32: 108104. https://doi.org/1016/j.celrep.2020.108104

[327]

Fedele L, Newcombe J, Topf M, et al., 2018, Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Commun, 9: 957. https://doi.org/1038/s41467-018-02927-4 

[328]

Glasgow NG, Retchless BS, Johnson JW, 2015, Molecular bases of NMDA receptor subtype-dependent properties. J Physiol, 593: 83–95. https://doi.org/1113/jphysiol.2014.273763

[329]

Andreoli V, De Marco EV, Trecroci F, et al., 2014, Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease. J Neural Transm, 121: 533–542. https://doi.org/1007/s00702-013-1125-7

[330]

Myers RA, Casals F, Gauthier J, et al., 2011, A population genetic approach to mapping neurological disorder genes using deep resequencing. PLoS Genet, 7: e1001318. https://doi.org/1371/journal.pgen.1001318

[331]

Hu C, Chen W, Myers SJ, et al., 2016, Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci, 132: 115–121. https://doi.org/1016/j.jphs.2016.10.002

[332]

Tarabeux J, Kebir O, Gauthier J, et al., 2011, Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry, 1: e55. https://doi.org/1038/tp.2011.52

[333]

Retterer K, Juusola J, Cho MT, et al., 2016, Clinical application of whole-exome sequencing across clinical indications. Genet Med, 18: 696–704. https://doi.org/1038/gim.2015.148

[334]

Wells G, Yuan H, McDaniel MJ, et al., 2018, The GluN2B-Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand-unbinding and domain opening. Proteins, 86: 1265–1276. https://doi.org/1002/prot.25595

[335]

Shin W, Kim K, Serraz B, et al., 2020, Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice. PLoS Biol, 18: e3000717. https://doi.org/1371/journal.pbio.3000717

[336]

Soto D, Olivella M, Grau C, et al., 2019, L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy. Sci Signal, 12: eaaw0936. https://doi.org/1126/scisignal.aaw0936 

[337]

Lemke JR, Hendrickx R, Geider K, et al., 2014, GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol, 75: 147–154. https://doi.org/1002/ana.24073

[338]

Mullier B, Wolff C, Sands ZA, et al., 2017, GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors. Neuropharmacology, 123: 322–331. https://doi.org/1016/j.neuropharm.2017.05.017

[339]

Li D, Yuan H, Ortiz-Gonzalez XR, et al., 2016, GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. Am J Human Genet, 99: 802–816. https://doi.org/1016/j.ajhg.2016.07.013

[340]

Chen HS, Lipton SA, 2006, The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem, 97: 1611–1626. https://doi.org/1111/j.1471-4159.2006.03991.x

Conflict of interest
The authors declare no competing interests.
Share
Back to top
Advanced Neurology, Electronic ISSN: 2810-9619 Published by AccScience Publishing