Key Points
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GluN3 subunits (A and B) were the last members of the glutamate receptor subunit family to be cloned. They assemble with GluN1 and GluN2 (A–D) subunits to form tri-heteromeric NMDA receptors (NMDARs). NMDARs containing the GluN3A subunit seem to counteract some of the well-known functions of classical NMDARs (GluN1–GluN2 di-heteromers) in long-term plasticity and synapse development.
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GluN3A-containing NMDARs are expressed during a narrow temporal window of early postnatal development and have been proposed to play a part in controlling the timing and extent of neural circuit refinements by acting as a 'brake' to prevent the premature strengthening and stabilization of subsets of excitatory synapses. Interactions of the carboxy-terminal domain of GluN3A with a unique set of intracellular partners are required for this function. In addition, GluN3A-containing NMDARs are much less permeable to Ca2+ ions and relatively insensitive to voltage-dependent block by Mg2+ compared with classical NMDARs.
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GluN3-containing NMDARs might also influence oligodendrocyte maturation and regulate forms of plasticity that are mediated by presynaptic NMDARs.
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Expression of GluN3A is reactivated in a number of neurological diseases, and emerging evidence suggests a major pathophysiological role of GluN3A in some of them, including Huntington disease, addiction and white matter damage.
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The therapeutic potential of targeting GluN3A-containing NMDARs or intracellular regulators of their trafficking or signalling is just beginning to be explored but might provide a rational alternative to previously attempted therapies that targeted the more ubiquitous GluN1 or GluN2 subunits.
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GluN3 subunits can assemble with only GluN1 subunits in heterologous cells to form surface-expressed di-heteromeric receptors that do not bind glutamate and function as excitatory glycine receptors, but the physiological significance of this function is not known.
Abstract
GluN3-containing NMDA receptors (GluN3-NMDARs) are rarer than the 'classical' NMDARs, which are composed solely of GluN1 and GluN2 subunits, and have non-conventional biophysical, trafficking and signalling properties. In the CNS, they seem to have important roles in delaying synapse maturation until the arrival of sensory experience and in targeting non-used synapses for pruning. The reactivation of GluN3A expression at inappropriate ages may underlie maladaptive synaptic rearrangements observed in addiction, neurodegenerative diseases and other major brain disorders. Here, we discuss current evidence for these and other emerging roles for GluN3-NMDARs in the physiology and pathology of the CNS.
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References
Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383–400 (2013).
Lau, C. G. & Zukin, R. S. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat. Rev. Neurosci. 8, 413–426 (2007).
Malenka, R. C. & Nicoll, R. A. Long-term potentiation--a decade of progress? Science 285, 1870–1874 (1999).
Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).
Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).
Eriksson, M. et al. Cloning and expression of the human N-methyl-d-aspartate receptor subunit NR3A. Neurosci. Lett. 321, 177–181 (2002).
Sucher, N. J. et al. Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J. Neurosci. 15, 6509–6520 (1995).
Ciabarra, A. M. et al. Cloning and characterization of χ-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J. Neurosci. 15, 6498–6508 (1995).
Andersson, O., Stenqvist, A., Attersand, A. & von Euler, G. Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics 78, 178–184 (2001).
Sun, L., Margolis, F. L., Shipley, M. T. & Lidow, M. S. Identification of a long variant of mRNA encoding the NR3 subunit of the NMDA receptor: its regional distribution and developmental expression in the rat brain. FEBS Lett. 441, 392–396 (1998).
Domingues, A. M., Neugebauer, K. M. & Fern, R. Identification of four functional NR3B isoforms in developing white matter reveals unexpected diversity among glutamate receptors. J. Neurochem. 117, 449–460 (2011).
Chatterton, J. E. et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798 (2002). This is the first study to show that GluN1–GluN3 complexes behave as excitatory glycine-gated receptors.
Nishi, M., Hinds, H., Lu, H. P., Kawata, M. & Hayashi, Y. Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner. J. Neurosci. 21, RC185 (2001).
Pérez-Otaño, I. et al. Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J. Neurosci. 21, 1228–1237 (2001). This paper reports the determinants for subunit assembly and forward trafficking of GluN3A-NMDARs.
Matsuda, K., Fletcher, M., Kamiya, Y. & Yuzaki, M. Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J. Neurosci. 23, 10064–10073 (2003).
Das, S. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998). This paper shows that lack of GluN3A leads to larger NMDAR currents and increases synapse density and size.
Sasaki, Y. F. et al. Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J. Neurophysiol. 87, 2052–2063 (2002). References 14, 16 and 17 describe the atypical biophysical properties of GluN3A-NMDARs.
Tong, G. et al. Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J. Neurophysiol. 99, 122–132 (2008).
Roberts, A. C. et al. Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63, 342–356 (2009). This study shows that prolonging juvenile levels of GluN3A into adulthood impairs synaptic connectivity and alters fundamental aspects of cognition.
Burzomato, V., Frugier, G., Pérez-Otaño, I., Kittler, J. T. & Attwell, D. The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes. J. Physiol. 588, 3403–3414 (2010).
Pachernegg, S., Strutz-Seebohm, N. & Hollmann, M. GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci. 35, 240–249 (2012).
Martinez-Turrillas, R. et al. The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation. Neurobiol. Dis. 48, 290–298 (2012).
Al-Hallaq, R. A. et al. Association of NR3A with the N-methyl-d-aspartate receptor NR1 and NR2 subunits. Mol. Pharmacol. 62, 1119–1127 (2002).
Nilsson, A. et al. Analysis of NR3A receptor subunits in human native NMDA receptors. Brain Res. 1186, 102–112 (2007).
Hansen, K. B., Ogden, K. K., Yuan, H. & Traynelis, S. F. Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81, 1084–1096 (2014).
Stroebel, D., Carvalho, S., Grand, T., Zhu, S. & Paoletti, P. Controlling NMDA receptor subunit composition using ectopic retention signals. J. Neurosci. 34, 16630–16636 (2014).
McClymont, D. W., Harris, J. & Mellor, I. R. Open-channel blockade is less effective on GluN3B than GluN3A subunit-containing NMDA receptors. Eur. J. Pharmacol. 686, 22–31 (2012).
Cavara, N. A. & Hollmann, M. Shuffling the deck anew: how NR3 tweaks NMDA receptor function. Mol. Neurobiol. 38, 16–26 (2008).
Low, C. M. & Wee, K. S. New insights into the not-so-new NR3 subunits of N-methyl-d-aspartate receptor: localization, structure, and function. Mol. Pharmacol. 78, 1–11 (2010).
Kehoe, L. A., Bernardinelli, Y. & Muller, D. GluN3A: an NMDA receptor subunit with exquisite properties and functions. Neural Plast. 2013, 145387 (2013).
Smothers, C. T. & Woodward, J. J. Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits. J. Pharmacol. Exp. Ther. 322, 739–748 (2007).
Cummings, K. A. & Popescu, G. K. Protons potentiate GluN1/GluN3A currents by attenuating their desensitisation. Sci. Rep. 6, 23344 (2016).
Pina-Crespo, J. C. et al. Excitatory glycine responses of CNS myelin mediated by NR1/NR3 “NMDA” receptor subunits. J. Neurosci. 30, 11501–11505 (2010).
Smothers, C. T. & Woodward, J. J. Effect of the NR3 subunit on ethanol inhibition of recombinant NMDA receptors. Brain Res. 987, 117–121 (2003).
Yao, Y. & Mayer, M. L. Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J. Neurosci. 26, 4559–4566 (2006).
Yao, Y., Harrison, C. B., Freddolino, P. L., Schulten, K. & Mayer, M. L. Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors. EMBO J. 27, 2158–2170 (2008).
Yao, Y., Belcher, J., Berger, A. J., Mayer, M. L. & Lau, A. Y. Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure 21, 1788–1799 (2013).
Kvist, T., Greenwood, J. R., Hansen, K. B., Traynelis, S. F. & Brauner-Osborne, H. Structure-based discovery of antagonists for GluN3-containing N-methyl-d-aspartate receptors. Neuropharmacology 75, 324–336 (2013).
Henson, M. A., Roberts, A. C., Pérez-Otaño, I. & Philpot, B. D. Influence of the NR3A subunit on NMDA receptor functions. Prog. Neurobiol. 91, 23–37 (2010).
Sucher, N. J. et al. N-Methyl-d-aspartate receptor subunit NR3A in the retina: developmental expression, cellular localization, and functional aspects. Invest. Ophthalmol. Vis. Sci. 44, 4451–4456 (2003).
Pfeffer, C. K., Xue, M., He, M., Huang, Z. J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat. Neurosci. 16, 1068–1076 (2013).
Wee, K. S., Zhang, Y., Khanna, S. & Low, C. M. Immunolocalization of NMDA receptor subunit NR3B in selected structures in the rat forebrain, cerebellum, and lumbar spinal cord. J. Comp. Neurol. 509, 118–135 (2008).
Wong, H. K. et al. Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain. J. Comp. Neurol. 450, 303–317 (2002).
Larsen, R. S. et al. Synapse-specific control of experience-dependent plasticity by presynaptic NMDA receptors. Neuron 83, 879–893 (2014). This paper reports that visual experience suppresses a presynaptic NMDAR form of t-LTD at synapses between neurons in visual cortex layer 4 and those in layer2/3 by downregulating GluN3A-NMDARs.
Ishihama, K. & Turman, J. E. Jr. NR3 protein expression in trigeminal neurons during postnatal development. Brain Res. 1095, 12–16 (2006).
Wee, K. S., Tan, F. C., Cheong, Y. P., Khanna, S. & Low, C. M. Ontogenic profile and synaptic distribution of GluN3 proteins in the rat brain and hippocampal neurons. Neurochem. Res. 41, 290–297 (2016).
Pérez-Otaño, I. et al. Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1. Nat. Neurosci. 9, 611–621 (2006). This article identifies a biological mechanism underlying the downregulation of GluN3A-NMDARs in synapses that involves the recruitment of PACSIN1, a selective endocytic adaptor. It additionally reports activity dependence of GluN3A endocytosis.
Racca, C., Stephenson, F. A., Streit, P., Roberts, J. D. & Somogyi, P. NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J. Neurosci. 20, 2512–2522 (2000).
Bard, L. et al. Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. Proc. Natl Acad. Sci. USA 107, 19561–19566 (2010).
Eriksson, M. et al. On the role of NR3A in human NMDA receptors. Physiol. Behav. 92, 54–59 (2007).
Henson, M. A. et al. Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS ONE 7, e42327 (2012).
Pérez-Otaño, I. & Ehlers, M. D. Learning from NMDA receptor trafficking: clues to the development and maturation of glutamatergic synapses. Neurosignals 13, 175–189 (2004).
Rogge, G. A., Singh, H., Dang, R. & Wood, M. A. HDAC3 is a negative regulator of cocaine-context-associated memory formation. J. Neurosci. 33, 6623–6632 (2013).
Rodenas-Ruano, A., Chávez, A. E., Cossio, M. J., Castillo, P. E. & Zukin, R. S. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat. Neurosci. 15, 1382–1390 (2012).
Wee, K. S., Wee, Z. N., Chow, N. B. & Low, C. M. The distal carboxyl terminal of rat NR3B subunit regulates NR1-1a/NR3B and NR1-2a/NR3B surface trafficking. Neurochem. Int. 57, 97–101 (2010).
Chowdhury, D. et al. Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors. J. Neurosci. 33, 4151–4164 (2013).
Holtmaat, A. J. et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45, 279–291 (2005).
Rakic, P., Bourgeois, J. P., Eckenhoff, M. F., Zecevic, N. & Goldman-Rakic, P. S. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 232, 232–235 (1986).
Zuo, Y., Lin, A., Chang, P. & Gan, W. B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005).
Gambrill, A. C. & Barria, A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc. Natl Acad. Sci. USA 108, 5855–5860 (2011).
Adesnik, H., Li, G., During, M. J., Pleasure, S. J. & Nicoll, R. A. NMDA receptors inhibit synapse unsilencing during brain development. Proc. Natl Acad. Sci. USA 105, 5597–5602 (2008).
Barria, A. & Malinow, R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 35, 345–353 (2002).
Bellone, C. & Nicoll, R. A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55, 779–785 (2007).
Philpot, B. D., Sekhar, A. K., Shouval, H. Z. & Bear, M. F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).
Nagerl, U. V., Eberhorn, N., Cambridge, S. B. & Bonhoeffer, T. Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron 44, 759–767 (2004).
Marco, S. et al. Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. Nat. Med. 19, 1030–1038 (2013). This study demonstrates a causal relationship between dysregulation of a key pathway for endocytic trafficking of GluN3A and aberrant synapse pruning in Huntington disease.
Kehoe, L. A. et al. GluN3A promotes dendritic spine pruning and destabilization during postnatal development. J. Neurosci. 34, 9213–9221 (2014). This paper describes a role for GluN3A in promoting synapse destabilization and elimination in hippocampal organotypic slices.
Sanes, J. R. & Lichtman, J. W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat. Rev. Neurosci. 2, 791–805 (2001).
Brody, S. A., Nakanishi, N., Tu, S., Lipton, S. A. & Geyer, M. A. A developmental influence of the N-methyl-D-aspartate receptor NR3A subunit on prepulse inhibition of startle. Biol. Psychiatry 57, 1147–1152 (2005).
Mohamad, O., Song, M. K., Wei, L. & Yu, S. P. Regulatory roles of the NMDA receptor GluN3A subunit in locomotion, pain perception and cognitive functions in adult mice. J. Physiol. 591, 149–168 (2013).
Bastrikova, N., Gardner, G. A., Reece, J. M., Jeromin, A. & Dudek, S. M. Synapse elimination accompanies functional plasticity in hippocampal neurons. Proc. Natl Acad. Sci. USA 105, 3123–3127 (2008).
Fiuza, M., González-González, I. & Pérez-Otaño, I. GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 signaling. Proc. Natl Acad. Sci. USA 110, 20807–20812 (2013). This paper reports an inhibitory role of GluN3A-NMDARs on spine rearrangements by diminishing the activation of the RAC1–PAK pathway in dendritic spines.
Sucher, N. J. et al. Association of the small GTPase Rheb with the NMDA receptor subunit NR3A. Neurosignals 18, 203–209 (2010).
Chan, S. F. & Sucher, N. J. An NMDA receptor signaling complex with protein phosphatase 2A. J. Neurosci. 21, 7985–7992 (2001).
Tang, G. et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83, 1131–1143 (2014).
Liu, E., Knutzen, C. A., Krauss, S., Schweiger, S. & Chiang, G. G. Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc. Natl Acad. Sci. USA 108, 8680–8685 (2011).
Eriksson, M. et al. The NMDAR subunit NR3A interacts with microtubule-associated protein 1S in the brain. Biochem. Biophys. Res. Commun. 361, 127–132 (2007).
Eriksson, M. et al. MAP1B binds to the NMDA receptor subunit NR3A and affects NR3A protein concentrations. Neurosci. Lett. 475, 33–37 (2010).
Larsen, R. S. et al. NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat. Neurosci. 14, 338–344 (2011).
Berg, L. K., Larsson, M., Morland, C. & Gundersen, V. Pre- and postsynaptic localization of NMDA receptor subunits at hippocampal mossy fibre synapses. Neuroscience 230, 139–150 (2013).
Salter, M. G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171 (2005).
Karadottir, R., Cavelier, P., Bergersen, L. H. & Attwell, D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438, 1162–1166 (2005).
Jantzie, L. L. et al. Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. Cereb. Cortex 25, 482–495 (2015). References 81–83 report the presence of GluN3A subunits in myelin-forming oligodendrocytes.
Micu, I. et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439, 988–992 (2006).
Lundgaard, I. et al. Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes. PLoS Biol. 11, e1001743 (2013). This article shows that oligodendrocyte processes express GluN3A-NMDARs. It demonstrates that BDNF and neuregulin downregulate GluN3A levels in oligodendrocytes, favouring activity-dependent myelination. The findings support a role for GluN3A downregulation in 'adaptive myelination'.
Micu, I. et al. The molecular physiology of the axo-myelinic synapse. Exp. Neurol. 276, 41–50 (2015).
De Biase, L. M. et al. NMDA receptor signaling in oligodendrocyte progenitors is not required for oligodendrogenesis and myelination. J. Neurosci. 31, 12650–12662 (2011).
Yuan, T. et al. Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 80, 1025–1038 (2013). This paper identifies GluN3A as an unexpected player in synaptic adaptations triggered by cocaine.
Mueller, H. T. & Meador-Woodruff, J. H. NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. Schizophr. Res. 71, 361–370 (2004).
Henson, M. A. et al. Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex. Cereb. Cortex 18, 2560–2573 (2008).
Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000).
Rao, J. S., Harry, G. J., Rapoport, S. I. & Kim, H. W. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol. Psychiatry 15, 384–392 (2010).
Shen, Y. C. et al. Exomic sequencing of the ionotropic glutamate receptor N-methyl-d-aspartate 3A gene (GRIN3A) reveals no association with schizophrenia. Schizophr. Res. 114, 25–32 (2009).
Takata, A. et al. A population-specific uncommon variant in GRIN3A associated with schizophrenia. Biol. Psychiatry 73, 532–539 (2013).
Gallinat, J. et al. Genetic variations of the NR3A subunit of the NMDA receptor modulate prefrontal cerebral activity in humans. J. Cogn. Neurosci. 19, 59–68 (2007).
Papenberg, G. et al. Dopamine and glutamate receptor genes interactively influence episodic memory in old age. Neurobiol. Aging 35, 1213.e3–1213.e8 (2014).
Ohi, K. et al. Glutamate networks implicate cognitive impairments in schizophrenia: genome-wide association studies of 52 cognitive phenotypes. Schizophr. Bull. 41, 909–918 (2015).
Greenwood, T. A. et al. Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. Am. J. Psychiatry 168, 930–946 (2011).
Matsuno, H. et al. A naturally occurring null variant of the NMDA type glutamate receptor NR3B subunit is a risk factor of schizophrenia. PLoS ONE 10, e0116319 (2015).
Niemann, S. et al. Motoneuron-specific NR3B gene: no association with ALS and evidence for a common null allele. Neurology 70, 666–676 (2008).
Jin, Z. et al. Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics. Front. Cell. Neurosci. 8, 11 (2014).
Spanagel, R. Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol. Rev. 89, 649–705 (2009).
Yang, J. et al. The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol. Psychiatry 20, 1467–1478 (2015).
Yuan, T. & Bellone, C. Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors. Eur. J. Pharmacol. 719, 107–111 (2013).
Wesseling, J. F. & Pérez-Otaño, I. Modulation of GluN3A expression in Huntington disease: a new N-methyl-d-aspartate receptor-based therapeutic approach? JAMA Neurol. 72, 468–473 (2015).
Mahfooz, K. et al. GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models. Neurobiol. Dis. 93, 47–56 (2016).
Costantine, M. M. et al. Association of polymorphisms in neuroprotection and oxidative stress genes and neurodevelopmental outcomes after preterm birth. Obstetr. Gynecol. 120, 542–550 (2012).
Nakanishi, N. et al. Neuroprotection by the NR3A subunit of the NMDA receptor. J. Neurosci. 29, 5260–5265 (2009).
Lee, J. H. et al. A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse. Am. J. Physiol. Cell Physiol. 308, C570–C577 (2015).
Fernandes, J. et al. In vitro ischemia triggers a transcriptional response to down-regulate synaptic proteins in hippocampal neurons. PLoS ONE 9, e99958 (2014).
Zhou, C., Sun, H., Klein, P. M. & Jensen, F. E. Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons. Front. Cell. Neurosci. 9, 362 (2015).
Fields, R. D. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat. Rev. Neurosci. 16, 756–767 (2015).
Niemann, S. et al. Genetic ablatio of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes. Eur. J. Neurosci. 26, 1407–1420 (2007).
Liu, H. P. et al. Genetic variation in N-methyl-D-aspartate receptor subunit NR3A but not NR3B influences susceptibility to alzheimer's disease. Dement. Geriatr. Cogn. Disord. 28, 521–527 (2009).
Kazmierski, J. et al. The assessment of the T102C polymorphism of the 5HT2a receptor gene, 3723G/A polymorphism of the NMDA receptor 3A subunit gene (GRIN3A) and 421C/A polymorphism of the NMDA receptor 2B subunit gene (GRIN2B) among cardiac surgery patients with and without delirium. Gen. Hosp. Psychiatry 36, 753–756 (2014).
Acknowledgements
The authors thank the members of their groups, as well as K. Hansen, C. Bellone and T. Karadottir for valuable discussion, and L. García-Rabaneda and M. Pérez-Otaño for help with the figures. Work in the authors' laboratories is funded by Spanish Ministry of Science grants (CSD2008-00005 to I.P.-O. and SAF2013-48983-R to I.P.-O. and J.F.W.), UTE project CIMA, Marató TV3 Foundation and the Beca Josefina Garre. R.S.L. is funded by the Allen Institute for Brain Science and wishes to thank the Allen Institute founders, P. G. Allen and J. Allen, for their vision, encouragement and support.
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Glossary
- Postsynaptic densities
-
(PSDs). Specializations on excitatory dendritic spines that were originally identified by electron microscopy. They contain glutamate receptors and many associated scaffolding and trafficking proteins that are crucial for excitatory synaptic transmission.
- Coincidence detection
-
A mechanism through which neurons encode information by detecting two nearly simultaneous inputs from distinct sources.
- Critical periods
-
Finite but modifiable developmental time windows during which sensory experience-mediated input provides information that is essential for normal maturation of sensory circuits.
- Single-channel conductance
-
The single-channel current divided by the electrical driving force. It refers to the number of charges flowing through a single open channel under a given transmembrane potential and is usually expressed in picoSiemens (10−12 S).
- Open probability
-
The probability of an individual ion channel being in the open state under a given condition, observed as the fraction of the time that an ionic current is flowing. The value can be between 0 and 1.
- Epigenetic changes
-
Changes in phenotype that are driven by changes in the regulation of gene expression or changes in the function of gene products rather than by a change in genotype. Examples of epigenetic events include DNA methylation, X-chromosome inactivation and embryonic pattern formation.
- Prepulse inhibition
-
A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. Deficits in prepulse inhibition have been observed in patients with schizophrenia as well as in patients with other psychiatric and neurological disorders.
- Non-synonymous variants
-
Coding-DNA variations that result in an altered amino acid sequence.
- Periventricular leukomalacia
-
A form of white matter injury characterized by ischaemia of white matter adjacent to the lateral ventricles. It is the most common cause of ischaemic brain injury in premature infants, leading to motor problems and developmental delays.
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Pérez-Otaño, I., Larsen, R. & Wesseling, J. Emerging roles of GluN3-containing NMDA receptors in the CNS. Nat Rev Neurosci 17, 623–635 (2016). https://doi.org/10.1038/nrn.2016.92
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DOI: https://doi.org/10.1038/nrn.2016.92
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