N-Methyl-d-aspartate receptors (NMDARs), encoded by GRIN genes, are ionotropic glutamate receptors playing a critical role in synaptic transmission, plasticity, and synapse development. Genome sequence analyses have identified variants in GRIN genes in patients with neurodevelopmental disorders, but the underlying disease mechanisms are not well understood. Here, we have created and evaluated a transgenic mouse line carrying a missense variant Grin2bL825V , corresponding to a de novo GRIN2B variant encoding GluN2B(L825V) found in a patient with intellectual disability (ID) and autism spectrum disorder (ASD). We used HEK293T cells expressing recombinant receptors and primary hippocampal neurons prepared from heterozygous Grin2bL825V/+ (L825V/+) and wild-type (WT) Grin2b+/+ (+/+) male and female mice to assess the functional impact of the variant. Whole-cell NMDAR currents were reduced in neurons from L825V/+ compared with +/+ mice. The peak amplitude of NMDAR-mediated evoked excitatory postsynaptic currents (NMDAR-eEPSCs) was unchanged, but NMDAR-eEPSCs in L825V/+ neurons had faster deactivation compared with +/+ neurons and were less sensitive to a GluN2B-selective antagonist ifenprodil. Together, these results suggest a decreased functional contribution of GluN2B subunits to synaptic NMDAR currents in hippocampal neurons from L825V/+ mice. The analysis of the GluN2B(L825V) subunit surface expression and synaptic localization revealed no differences compared with WT GluN2B. Behavioral testing of mice of both sexes demonstrated hypoactivity, anxiety, and impaired sensorimotor gating in the L825V/+ strain, particularly affecting males, as well as cognitive symptoms. The heterozygous L825V/+ mouse offers a clinically relevant model of GRIN2B-related ID/ASD, and our results suggest synaptic-level functional changes that may contribute to neurodevelopmental pathology.

3rd Faculty of Medicine Charles University Prague 10000 Czech Republic

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec 25050 Czech Republic

Faculty of Science Charles University Prague 12800 Czech Republic

Institute of Biotechnology of the Czech Academy of Sciences Vestec 25050 Czech Republic

Institute of Physiology of the Czech Academy of Sciences Prague 14220 Czech Republic

Proteomics Core Facility Faculty of Science Charles University Biocev Vestec 25050 Czech Republic

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Akashi K, Kakizaki T, Kamiya H, Fukaya M, Yamasaki M, Abe M, Natsume R, Watanabe M, Sakimura K (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. 10.1523/JNEUROSCI.5531-08.2009 PubMed DOI PMC

Al-Hallaq RA, Conrads TP, Veenstra TD, Wenthold RJ (2007) NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J Neurosci 27:8334–8343. 10.1523/JNEUROSCI.2155-07.2007 PubMed DOI PMC

Alvarez VA, Ridenour DA, Sabatini BL (2007) Distinct structural and ionotropic roles of NMDA receptors in controlling spine and synapse stability. J Neurosci 27:7365–7376. 10.1523/JNEUROSCI.0956-07.2007 PubMed DOI PMC

Amin JB, Leng X, Gochman A, Zhou HX, Wollmuth LP (2018) A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca(2+) permeability. Nat Commun 9:3748. 10.1038/s41467-018-06145-w PubMed DOI PMC

Amin JB, Moody GR, Wollmuth LP (2021) From bedside-to-bench: what disease-associated variants are teaching us about the NMDA receptor. J Physiol 599:397–416. 10.1113/JP278705 PubMed DOI PMC

Awadalla P, et al. (2010) Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am J Hum Genet 87:316–324. 10.1016/j.ajhg.2010.07.019 PubMed DOI PMC

Ayabe S, Nakashima K, Yoshiki A (2019) Off- and on-target effects of genome editing in mouse embryos. J Reprod Develop 65:1–5. 10.1262/jrd.2018-128 PubMed DOI PMC

Bar-Shira O, Maor R, Chechik G (2015) Gene expression switching of receptor subunits in human brain development. PLoS Comput Biol 11:e1004559. 10.1371/journal.pcbi.1004559 PubMed DOI PMC

Barria A, Malinow R (2005) NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48:289–301. 10.1016/j.neuron.2005.08.034 PubMed DOI

Benke TA, Park K, Krey I, Camp CR, Song R, Ramsey AJ, Yuan H, Traynelis SF, Lemke J (2021) Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs. Neuropharmacology 199:108805. 10.1016/j.neuropharm.2021.108805 PubMed DOI PMC

Benner S, Endo T, Endo N, Kakeyama M, Tohyama C (2014) Early deprivation induces competitive subordinance in C57BL/6 male mice. Physiol Behav 137:42–52. 10.1016/j.physbeh.2014.06.018 PubMed DOI

Bey AL, Jiang YH (2014) Overview of mouse models of autism spectrum disorders. Curr Protoc Pharmacol 66:5.66.1–5.66.26. 10.1002/0471141755.ph0566s66 PubMed DOI PMC

Brooks BR, et al. (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614. 10.1002/jcc.21287 PubMed DOI PMC

Cais O, Sedlacek M, Horak M, Dittert I, Vyklicky L Jr (2008) Temperature dependence of NR1/NR2B NMDA receptor channels. Neuroscience 151:428–438. 10.1016/j.neuroscience.2007.11.002 PubMed DOI

Cerny J, Bozikova P, Balik A, Marques SM, Vyklicky L (2019) NMDA receptor opening and closing-transitions of a molecular machine revealed by molecular dynamics. Biomolecules 9:546. 10.3390/biom9100546 PubMed DOI PMC

Chen W, et al. (2017) GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function. J Hum Genet 62:589–597. 10.1038/jhg.2017.19 PubMed DOI PMC

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

Doerr S, Harvey MJ, Noe F, De Fabritiis G (2016) HTMD: high-throughput molecular dynamics for molecular discovery. J Chem Theory Comput 12:1845–1852. 10.1021/acs.jctc.6b00049 PubMed DOI

Dupuis JP, et al. (2014) Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses. EMBO J 33:842–861. 10.1002/embj.201386356 PubMed DOI PMC

Elmasri M, Hunter DW, Winchester G, Bates EE, Aziz W, Van Der Does DM, Karachaliou E, Sakimura K, Penn AC (2022a) Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A. Commun Biol 5:174. 10.1038/s42003-022-03115-3 PubMed DOI PMC

Elmasri M, Lotti JS, Aziz W, Steele OG, Karachaliou E, Sakimura K, Hansen KB, Penn AC (2022b) Synaptic dysfunction by mutations in GRIN2B: influence of triheteromeric NMDA receptors on gain-of-function and loss-of-function mutant classification. Brain Sci 12:789. 10.3390/brainsci12060789 PubMed DOI PMC

Erreger K, et al. (2007) Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl- d-aspartate glutamate receptors. Mol Pharmacol 72:907–920. 10.1124/mol.107.037333 PubMed DOI

Erreger K, Dravid SM, Banke TG, Wyllie DJ, Traynelis SF (2005) Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J Physiol 563:345–358. 10.1113/jphysiol.2004.080028 PubMed DOI PMC

Gambrill AC, Barria A (2011) NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A 108:5855–5860. 10.1073/pnas.1012676108 PubMed DOI PMC

Garcia-Nafria J, Watson JF, Greger IH (2016) IVA cloning: a single-tube universal cloning system exploiting bacterial in vivo assembly. Sci Rep 6:27459. 10.1038/srep27459 PubMed DOI PMC

Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA (2011) Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 71:1085–1101. 10.1016/j.neuron.2011.08.007 PubMed DOI PMC

Hall BJ, Ripley B, Ghosh A (2007) NR2B signaling regulates the development of synaptic AMPA receptor current. J Neurosci 27:13446–13456. 10.1523/JNEUROSCI.3793-07.2007 PubMed DOI PMC

Hansen KB, et al. (2021) Structure, function, and pharmacology of glutamate receptor ion channels. Pharmacol Rev 73:298–487. 10.1124/pharmrev.120.000131 PubMed DOI PMC

Hansen KB, Ogden KK, Yuan H, Traynelis SF (2014) Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81:1084–1096. 10.1016/j.neuron.2014.01.035 PubMed DOI PMC

Hanson JE, Yuan H, Perszyk RE, Banke TG, Xing H, Tsai MC, Menniti FS, Traynelis SF (2024) Therapeutic potential of N-methyl- d-aspartate receptor modulators in psychiatry. Neuropsychopharmacology 49:51–66. 10.1038/s41386-023-01614-3 PubMed DOI PMC

Hattier MA, Matson JL, Belva BC, Horovitz M (2011) The occurrence of challenging behaviours in children with autism spectrum disorders and atypical development. Dev Neurorehabil 14:221–229. 10.3109/17518423.2011.573836 PubMed DOI

Hatton CJ, Paoletti P (2005) Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron 46:261–274. 10.1016/j.neuron.2005.03.005 PubMed DOI

Horak M, Petralia RS, Kaniakova M, Sans N (2014) ER to synapse trafficking of NMDA receptors. Front Cell Neurosci 8:394. 10.3389/fncel.2014.00394 PubMed DOI PMC

Hu C, Chen W, Myers SJ, Yuan H, Traynelis SF (2016) Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci 132:115–121. 10.1016/j.jphs.2016.10.002 PubMed DOI PMC

Huettner JE, Bean BP (1988) Block of N-methyl- d-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci U S A 85:1307–1311. 10.1073/pnas.85.4.1307 PubMed DOI PMC

Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33. 10.1016/0263-7855(96)00018-5 PubMed DOI

Ishihama Y, Rappsilber J, Mann M (2006) Modular stop and go extraction tips with stacked disks for parallel and multidimensional peptide fractionation in proteomics. J Proteome Res 5:988–994. 10.1021/pr050385q PubMed DOI

Jahr CE (1992) High probability opening of NMDA receptor channels by l-glutamate. Science 255:470–472. 10.1126/science.1346477 PubMed DOI

Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem 29:1859–1865. 10.1002/jcc.20945 PubMed DOI

Karakas E, Furukawa H (2014) Crystal structure of a heterotetrameric NMDA receptor ion channel. Science 344:992–997. 10.1126/science.1251915 PubMed DOI PMC

Kellermayer B, et al. (2018) Differential nanoscale topography and functional role of GluN2-NMDA receptor subtypes at glutamatergic synapses. Neuron 100:106. 10.1016/j.neuron.2018.09.012 PubMed DOI

Kiryk A, Janusz A, Zglinicki B, Turkes E, Knapska E, Konopka W, Lipp HP, Kaczmarek L (2020) IntelliCage as a tool for measuring mouse behavior - 20 years perspective. Behav Brain Res 388:112620. 10.1016/j.bbr.2020.112620 PubMed DOI

Kobayashi Y, et al. (2013) Genetic dissection of medial habenula-interpeduncular nucleus pathway function in mice. Front Behav Neurosci 7:17. 10.3389/fnbeh.2013.00017 PubMed DOI PMC

Korinek M, et al. (2015) Cholesterol modulates open probability and desensitization of NMDA receptors. J Physiol 593:2279–2293. 10.1113/jphysiol.2014.288209 PubMed DOI PMC

Kuchtiak V, Smejkalova T, Horak M, Vyklicky L, Balik A (2024) Analysis of surface expression of NMDAR subunits in primary hippocampal neurons. In: NMDA receptors: methods in molecular biology (Burnashev N, Szepetowski P, eds), pp 29–46. New York: Humana. PubMed

Kulak NA, Geyer PE, Mann M (2017) Loss-less nano-fractionator for high sensitivity, high coverage proteomics. Mol Cell Proteomics 16:694–705. 10.1074/mcp.O116.065136 PubMed DOI PMC

Kulesskaya N, Voikar V (2014) Assessment of mouse anxiety-like behavior in the light–dark box and open-field arena: role of equipment and procedure. Physiol Behav 133:30–38. 10.1016/j.physbeh.2014.05.006 PubMed DOI

Kutsuwada T, et al. (1996) Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 16:333–344. 10.1016/S0896-6273(00)80051-3 PubMed DOI

Kysilov B, Hrcka Krausova B, Vyklicky V, Smejkalova T, Korinek M, Horak M, Chodounska H, Kudova E, Cerny J, Vyklicky L (2022) Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations. Br J Pharmacol 179:3970–3990. 10.1111/bph.15841 PubMed DOI

Ladislav M, Cerny J, Krusek J, Horak M, Balik A, Vyklicky L (2018) The LILI motif of M3-S2 linkers is a component of the NMDA receptor channel gate. Front Mol Neurosci 11:113. 10.3389/fnmol.2018.00113 PubMed DOI PMC

Laube B, Hirai H, Sturgess M, Betz H, Kuhse J (1997) Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron 18:493–503. 10.1016/S0896-6273(00)81249-0 PubMed DOI

Lazaridis T (2003) Effective energy function for proteins in lipid membranes. Proteins 52:176–192. 10.1002/prot.10410 PubMed DOI

Le T, Zarsky V, Nyvltova E, Rada P, Harant K, Vancova M, Verner Z, Hrdy I, Tachezy J (2020) Anaerobic peroxisomes in Mastigamoeba balamuthi. Proc Natl Acad Sci U S A 117:2065–2075. 10.1073/pnas.1909755117 PubMed DOI PMC

Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, Wei S, Buckner J, Jeong JC, Qi Y (2016) CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J Chem Theory Comput 12:405–413. 10.1021/acs.jctc.5b00935 PubMed DOI PMC

Lee C-H, Lü W, Michel JC, Goehring A, Du J, Song X, Gouaux E (2014) NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511:191–197. 10.1038/nature13548 PubMed DOI PMC

Liu S, Zhou L, Yuan H, Vieira M, Sanz-Clemente A, Badger JD 2nd, Lu W, Traynelis SF, Roche KW (2017) A rare variant identified within the GluN2B C-terminus in a patient with autism affects NMDA receptor surface expression and spine density. J Neurosci 37:4093–4102. 10.1523/JNEUROSCI.0827-16.2017 PubMed DOI PMC

Luo J, Wang Y, Yasuda RP, Dunah AW, Wolfe BB (1997) The majority of N-methyl- d-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B). Mol Pharmacol 51:79–86. 10.1124/mol.51.1.79 PubMed DOI

Masuda T, Tomita M, Ishihama Y (2008) Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. J Proteome Res 7:731–740. 10.1021/pr700658q PubMed DOI

Mayes SD, Becker SP, Calhoun SL, Waschbusch DA (2023) Comparison of the cognitive disengagement and hypoactivity components of sluggish cognitive tempo in autism, ADHD, and population-based samples of children. Res Child Adolesc Psychopathol 51:47–54. 10.1007/s10802-022-00969-3 PubMed DOI

McAlister GC, Nusinow DP, Jedrychowski MP, Wuhr M, Huttlin EL, Erickson BK, Rad R, Haas W, Gygi SP (2014) Multinotch MS3 enables accurate, sensitive, and multiplexed detection of differential expression across cancer cell line proteomes. Anal Chem 86:7150–7158. 10.1021/ac502040v PubMed DOI PMC

Mennerick S, Zorumski CF (1995) Paired-pulse modulation of fast excitatory synaptic currents in microcultures of rat hippocampal neurons. J Physiol 488:85–101. 10.1113/jphysiol.1995.sp020948 PubMed DOI PMC

Philpot BD, Weisberg MP, Ramos MS, Sawtell NB, Tang YP, Tsien JZ, Bear MF (2001) Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in visual cortex. Neuropharmacology 41:762–770. 10.1016/S0028-3908(01)00136-8 PubMed DOI

Platzer K, et al. (2017) GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 54:460–470. 10.1136/jmedgenet-2016-104509 PubMed DOI PMC

Rauner C, Kohr G (2011) Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl- d-aspartate receptor population in adult hippocampal synapses. J Biol Chem 286:7558–7566. 10.1074/jbc.M110.182600 PubMed DOI PMC

Rosenmund C, Feltz A, Westbrook GL (1995) Synaptic NMDA receptor channels have a low open probability. J Neurosci 15:2788–2795. 10.1523/JNEUROSCI.15-04-02788.1995 PubMed DOI PMC

Sauer AK, Hagmeyer S, Grabrucker AM (2022) Prenatal zinc deficient mice as a model for autism spectrum disorders. Int J Mol Sci 23:6082. 10.3390/ijms23116082 PubMed DOI PMC

Sceniak MP, Fedder KN, Wang Q, Droubi S, Babcock K, Patwardhan S, Wright-Zornes J, Pham L, Sabo SL (2019) An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth. J Cell Sci 132:jcs232892. 10.1242/jcs.232892 PubMed DOI

Scherer MK, Trendelkamp-Schroer B, Paul F, Perez-Hernandez G, Hoffmann M, Plattner N, Wehmeyer C, Prinz JH, Noe F (2015) PyEMMA 2: a software package for estimation, validation, and analysis of Markov models. J Chem Theory Comput 11:5525–5542. 10.1021/acs.jctc.5b00743 PubMed DOI

Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L (2005) The FoldX web server: an online force field. Nucleic Acids Res 33:W382–W388. 10.1093/nar/gki387 PubMed DOI PMC

Serraz B, Grand T, Paoletti P (2016) Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations. Neuropharmacology 109:196–204. 10.1016/j.neuropharm.2016.06.008 PubMed DOI

Sheng M, Cummings J, Roldan LA, Jan YN, Jan LY (1994) Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368:144–147. 10.1038/368144a0 PubMed DOI

Shin W, 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. 10.1371/journal.pbio.3000717 PubMed DOI PMC

Smejkalova T, Korinek M, Krusek J, Hrcka Krausova B, Candelas Serra M, Hajdukovic D, Kudova E, Chodounska H, Vyklicky L (2021) Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms. Br J Pharmacol 178:3888–3904. 10.1111/bph.15529 PubMed DOI PMC

Sprengel R, et al. (1998) Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92:279–289. 10.1016/S0092-8674(00)80921-6 PubMed DOI

Stiedl O, Radulovic J, Lohmann R, Birkenfeld K, Palve M, Kammermeier J, Sananbenesi F, Spiess J (1999) Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice. Behav Brain Res 104:1–12. 10.1016/S0166-4328(99)00047-9 PubMed DOI

Stroebel D, Carvalho S, Grand T, Zhu SJ, Paoletti P (2014) Controlling NMDA receptor subunit composition using ectopic retention signals. J Neurosci 34:16630–16636. 10.1523/JNEUROSCI.2736-14.2014 PubMed DOI PMC

Stroebel D, Casado M, Paoletti P (2018) Triheteromeric NMDA receptors: from structure to synaptic physiology. Curr Opin Physiol 2:1–12. 10.1016/j.cophys.2017.12.004 PubMed DOI PMC

Swanger SA, 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. 10.1016/j.ajhg.2016.10.002 PubMed DOI PMC

Tarabeux J, et al. (2011) Rare mutations in N-methyl- d-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry 1:e55. 10.1038/tp.2011.52 PubMed DOI PMC

Tovar KR, McGinley MJ, Westbrook GL (2013) Triheteromeric NMDA receptors at hippocampal synapses. J Neurosci 33:9150–9160. 10.1523/JNEUROSCI.0829-13.2013 PubMed DOI PMC

Tovar KR, Westbrook GL (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 19:4180–4188. 10.1523/JNEUROSCI.19-10-04180.1999 PubMed DOI PMC

Turecek R, Vlcek K, Petrovic M, Horak M, Vlachova V, Vyklicky L Jr (2004) Intracellular spermine decreases open probability of N-methyl- d-aspartate receptor channels. Neuroscience 125:879–887. 10.1016/j.neuroscience.2004.03.003 PubMed DOI

Tyanova S, Cox J (2018) Perseus: a bioinformatics platform for integrative analysis of proteomics data in cancer research. Methods Mol Biol 1711:133–148. 10.1007/978-1-4939-7493-1_7 PubMed DOI

UniProt C (2021) UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res 49:D480–D489. 10.1093/nar/gkaa1100 PubMed DOI PMC

Uzunova G, Hollander E, Shepherd J (2014) The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome. Curr Neuropharmacol 12:71–98. 10.2174/1570159X113116660046 PubMed DOI PMC

Vieira M, Yong XLH, Roche KW, Anggono V (2020) Regulation of NMDA glutamate receptor functions by the GluN2 subunits. J Neurochem 154:121–143. 10.1111/jnc.14970 PubMed DOI PMC

Vyklicky V, et al. (2018) Surface expression, function, and pharmacology of disease-associated mutations in the membrane domain of the human GluN2B subunit. Front Mol Neurosci 11:110. 10.3389/fnmol.2018.00110 PubMed DOI PMC

Vyklicky V, Korinek M, Balik A, Smejkalova T, Krausova B, Vyklicky L (2016) Analysis of whole-cell NMDA receptor currents. In: Ionotropic glutamate receptor technologies. Neuromethods (Popescu G, ed) Vol. 106, pp. 205–219. New York, NY: Humana Press. 10.1007/978-1-4939-2812-5_14 DOI

Wang CC, Held RG, Chang SC, Yang LL, Delpire E, Ghosh A, Hall BJ (2011) A critical role for GluN2B-containing NMDA receptors in cortical development and function. Neuron 72:789–805. 10.1016/j.neuron.2011.09.023 PubMed DOI

Webb B, Sali A (2014) Comparative protein structure modeling using MODELLER. Curr Protoc Bioinformatics 47:5.6.1–5.6.37. 10.1002/0471250953.bi0506s47 PubMed DOI

White SW, Oswald D, Ollendick T, Scahill L (2009) Anxiety in children and adolescents with autism spectrum disorders. Clin Psychol Rev 29:216–229. 10.1016/j.cpr.2009.01.003 PubMed DOI PMC

Williams K (1993) Ifenprodil discriminates subtypes of the N-methyl- d-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol 44:851–859. PubMed

Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology