NMDA receptor

File:Activated NMDAR.PNG
Stylised depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site. Allosteric sites that would cause inhibition of the receptor are not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine.[1]

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel protein found in nerve cells. It is activated when glutamate and glycine (or D-serine) bind to it, and when activated it allows positively charged ions to flow through the cell membrane.[2] The NMDA receptor is very important for controlling synaptic plasticity and memory function.[3]

The NMDAR is a specific type of ionotropic glutamate receptor. The NMDA receptor is named this because the agonist molecule N-methyl-D-aspartate (NMDA) binds selectively to it, and not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations with a reversal potential near 0 mV. A property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg2+ & Zn2+ ions. This allows the flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell to be voltage-dependent.[4][5][6][7]

Calcium flux through NMDARs is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in two ways: first, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands: glutamate and either D-serine or glycine.[8]

The activity of the NMDA receptor is affected by many psychoactive drugs such as phencyclidine (PCP), alcohol (ethanol) and dextromethorphan (DXM). The anaesthetic effects of the drugs ketamine and nitrous oxide are partially because of their effects on NMDA receptor activity.


The NMDA receptor forms a heterotetramer between two GluN1 and two GluN2 subunits (the subunits were previously denoted as NR1 and NR2), two obligatory NR1 subunits and two regionally localized NR2 subunits. A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits.

Each receptor subunit has modular design and each structural module also represents a functional unit:

  • The extracellular domain contains two globular structures: a modulatory domain and a ligand-binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate.
  • The agonist-binding module links to a membrane domain, which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels.
  • The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary conductance, high-calcium permeability, and voltage-dependent magnesium block.
  • Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.

The glycine-binding modules of the NR1 and NR3 subunits and the glutamate-binding module of the NR2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors.



There are eight variants of the NR1 subunit produced by alternative splicing of GRIN1:[9]

  • NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form.
  • NR1-2a, NR1-2b;
  • NR1-3a, NR1-3b;
  • NR1-4a, NR1-4b;


File:Model of NR2 Subunit of NMDA receptor (vertebrate and invertebrate).jpg
NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008

While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2 subunit are expressed in vertebrates and are referred to with the nomenclature NR2A through D(coded by GRIN2A, GRIN2B, GRIN2C, GRIN2D). Strong evidence shows that the genes coding the NR2 subunits in vertebrates have undergone at least two rounds of gene duplication.[10] They contain the binding-site for the neurotransmitter glutamate. More importantly, each NR2 subunit has a different intracellular C-terminal domain that can interact with different sets of signalling molecules.[11] Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil.

Whereas NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor.[12] For instance, greater ratios of the NR2B subunit leads to NMDA receptors which remain open longer compared to those with more NR2A.[13] This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically-altered 'doogie mice'.

There are three hypothetical models to describe this switch mechanism:

  • Dramatic increase in synaptic NR2A along with decrease in NR2B
  • Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A
  • Increase of NR2A diluting the number of NR2B without the decrease of the latter.

The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death.[14] The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.[15] Disruption of the gene for NR2B in mice causes perinatal lethality, whereas the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity.[16] One study suggests that reelin may play a role in the NMDA receptor maturation by increasing the NR2B subunit mobility.[17]

NR2B to NR2C switch

Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division[18] in the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they downregulate NR2B and activate NR2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors.[19]



Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly).[20] In addition, NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor.

D-serine has also been found to co-agonize the NMDA receptor with even greater potency than glycine.[21] D-serine is produced by serine racemase, and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine can be released both by neurons and astrocytes to regulate NMDA receptors.

NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast Mg2+ unbinding kinetics, increasing channel open probability with depolarization. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

Some known NMDA receptor agonists include:

Partial agonists

Glycine-site NMDA receptor partial agonists, such as rapastinel and NRX-1074, are now viewed with great interest for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.[23]


Antagonists of the NMDA receptor are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs due to their hallucinogenic properties, in addition to their unique effects at elevated dosages such as dissociation. When certain NMDA receptor antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's lesions. NMDA receptor antagonists that have been shown to induce Olney's lesions include ketamine, phencyclidine, and dextrorphan (a metabolite of dextromethorphan), as well as some NMDA receptor antagonists used only in research environments. So far, the published research on Olney's lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists.[24]

Common agents in which NMDA receptor antagonism is the primary mechanism of action:

Some common agents in which weak NMDA receptor antagonism is a secondary or additional action include:

Kynurenic acid is an endogenous NMDA receptor antagonist.


The NMDA receptor is modulated by a number of endogenous and exogenous compounds:[27]

  • Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.
  • Zn2+ and Cu2+ generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity. [28]
  • Pb2+[29] is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb2+ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.
  • It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.
  • Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.
  • The activity of NMDA receptors is also strikingly sensitive to the changes in H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions. [30] The level of inhibition by H+ is greatly reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action.
  • NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site."[31] Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone.
  • Src kinase enhances NMDA receptor currents.[32]

Receptor modulation

The NMDA receptor is a non-specific cation channel that can allow the passage of Ca2+ and Na+ into the cell and K+ out of the cell. The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function as a second messenger in various signaling pathways. However, the NMDA receptor cation channel is blocked by Mg2+ at resting membrane potential. To unblock the channel, the postsynaptic cell must be depolarized.[39]

Therefore, the NMDA receptor functions as a "molecular coincidence detector". Its ion channel opens only when the following two conditions are met simultaneously: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg2+ blocking the channel). This property of the NMDA receptor explains many aspects of long-term potentiation (LTP) and synaptic plasticity.[40]

NMDA receptors are modulated by a number of endogenous and exogenous compounds and play a key role in a wide range of physiological (e.g., memory) and pathological processes (e.g., excitotoxicity).

Clinical significance

Memantine is approved by the U.S. F.D.A and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease,[41] and has now received a limited recommendation by the UK's National Institute for Health and Care Excellence for patients who fail other treatment options.[42]

Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat tinnitus. Recently, NMDARs were associated with a rare autoimmune disease, anti-NMDAR encephalitis, that usually occurs due to cross reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in teratoma.

NMDAR modulators, including esketamine, rapastinel, NRX-1074, and CERC-301, are under development for the treatment of mood disorders, including major depressive disorder and treatment-resistant depression.[43] In addition, ketamine is already employed for this purpose as an off-label therapy in some clinics.[44][45]

Compared to dopaminergic stimulants, phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the glutamate hypothesis of schizophrenia.[46] Experiments in which rodents are treated with NMDA receptor antagonist are today the most common model when it comes to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs already approved for treatment of schizophrenia.

See also

External links


  1. ^ 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 (3): 493–503. PMID 9115742. doi:10.1016/S0896-6273(00)81249-0. 
  2. ^ "Subunit arrangement and function in NMDA receptors". Nature 438 (7065): 185–92. November 2005. PMID 16281028. doi:10.1038/nature04089. Retrieved February 12, 2015.  |first1= missing |last1= in Authors list (help)
  3. ^ Li F, Tsien JZ (2009). "Memory and the NMDA receptors". N. Engl. J. Med. 361 (3): 302–3. PMC 3703758. PMID 19605837. doi:10.1056/NEJMcibr0902052. 
  4. ^ Dingledine R, Borges K, Bowie D, Traynelis SF (March 1999). "The glutamate receptor ion channels". Pharmacol. Rev. 51 (1): 7–61. PMID 10049997. 
  5. ^ Liu Y, Zhang J (October 2000). "Recent development in NMDA receptors". Chin. Med. J. 113 (10): 948–56. PMID 11775847. 
  6. ^ Cull-Candy S, Brickley S, Farrant M (June 2001). "NMDA receptor subunits: diversity, development and disease". Curr. Opin. Neurobiol. 11 (3): 327–35. PMID 11399431. doi:10.1016/S0959-4388(00)00215-4. 
  7. ^ Paoletti P, Neyton J (February 2007). "NMDA receptor subunits: function and pharmacology". Curr Opin Pharmacol 7 (1): 39–47. PMID 17088105. doi:10.1016/j.coph.2006.08.011. 
  8. ^ Kleckner NW, Dingledine R (August 1988). "Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes". Science 241 (4867): 835–7. PMID 2841759. doi:10.1126/science.2841759. 
  9. ^ Stephenson FA (November 2006). "Structure and trafficking of NMDA and GABAA receptors" (PDF). Biochem. Soc. Trans. 34 (Pt 5): 877–81. PMID 17052219. doi:10.1042/BST0340877. 
  10. ^ Teng H. J., Cai W.S., Zhou L.L, Zhang J., Liu Q., Wang Y.Q., Dai W., Zhao M., Sun Z.S. et al. (2010). Desalle, Robert, ed. "Evolutionary Mode and Functional Divergence of Vertebrate NMDA Receptor Subunit 2 Genes". PLoS ONE 5 (10): e13342. doi:10.1371/journal.pone.0013342. 
  11. ^ Ryan, T. J. & Grant, S. G. N. (2009) The origin and evolution of synapses (vol 10, pg 701, 2009). Nat Rev Neurosci 10, Doi 10.1038/Nrn2748
  12. ^ Liu XB, Murray KD, Jones EG (October 2004). "Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development". J. Neurosci. 24 (40): 8885–95. PMID 15470155. doi:10.1523/JNEUROSCI.2476-04.2004. 
  13. ^ last, first (April 2000). "title". Scientific American. 
  14. ^ Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (March 2007). "NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo". J. Neurosci. 27 (11): 2846–57. PMID 17360906. doi:10.1523/JNEUROSCI.0116-07.2007. 
  15. ^ Zhou M, Baudry M (March 2006). "Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors". J. Neurosci. 26 (11): 2956–63. PMID 16540573. doi:10.1523/JNEUROSCI.4299-05.2006. 
  16. ^ Sprengel R. et al. (1998). "Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo". Cell 92 (2): 279–289. PMID 9458051. doi:10.1016/S0092-8674(00)80921-6.  |first2= missing |last2= in Authors list (help); |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help); |first9= missing |last9= in Authors list (help); |first10= missing |last10= in Authors list (help); |first11= missing |last11= in Authors list (help); |first12= missing |last12= in Authors list (help); |first13= missing |last13= in Authors list (help); |first14= missing |last14= in Authors list (help); |first15= missing |last15= in Authors list (help); |first16= missing |last16= in Authors list (help); |first17= missing |last17= in Authors list (help); |first18= missing |last18= in Authors list (help); |first19= missing |last19= in Authors list (help); |first20= missing |last20= in Authors list (help)
  17. ^ Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P (2007). "NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin". J. Neurosci. 27 (38): 10165–75. PMID 17881522. doi:10.1523/JNEUROSCI.1772-07.2007. 
  18. ^ Espinosa JS, Luo LJ (March 2008). "Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells". J. Neurosci. 28 (10): 2301–12. PMC 2586640. PMID 18322077. doi:10.1523/JNEUROSCI.5157-07.2008. 
  19. ^ Gajendran N, Kapfhammer JP, Lain E, Canepari M, Vogt K, Wisden W,Brenner HR (February 2009). "Neuregulin Signaling Is Dispensable for NMDA- and GABAA-Receptor Expression in the Cerebellum In Vivo". J. Neurosci. 29 (8): 2404–13. PMID 19244516. doi:10.1523/JNEUROSCI.4303-08.2009. 
  20. ^ Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ (May 2005). "Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling". Mol. Pharmacol. 67 (5): 1470–84. PMID 15703381. doi:10.1124/mol.104.008185. 
  21. ^ Wolosker H (Oct 2006). "D-serine regulation of NMDA receptor activity". Sci. STKE pe41 (356): 1–3. PMID 17033043. doi:10.1126/stke.3562006pe41. 
  22. ^ Yarotskyy V, Glushakov AV, Sumners C, Gravenstein N, Dennis DM, Seubert CN, Martynyuk AE (May 2005). "Differential modulation of glutamatergic transmission by 3,5-dibromo-L-phenylalanine". Mol. Pharmacol. 67 (5): 1648–54. PMID 15687225. doi:10.1124/mol.104.005983. 
  23. ^ J. Moskal, D. Leander, R. Burch (2010). Unlocking the Therapeutic Potential of the NMDA Receptor. Drug Discovery & Development News. Retrieved 19 December 2013.
  24. ^ Anderson C (2003-06-01). "The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid DXM Vaults : Health. Retrieved 2008-12-17. 
  25. ^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy". 2005-09-01. Retrieved 2008-12-17. 
  26. ^ "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations". British Journal of Pharmacology. 2013-05-08. Retrieved 2010-03-02. 
  27. ^ Huggins DJ, Grant GH (January 2005). "The function of the amino terminal domain in NMDA receptor modulation". J. Mol. Graph. Model. 23 (4): 381–8. PMID 15670959. doi:10.1016/j.jmgm.2004.11.006. 
  28. ^ "Zinc and Copper Influence Excitability of Rat Olfactory Bulb Neurons by Multiple Mechanisms". 
  29. ^ Toxicol. Sci. 116: 249–263. 2010. doi:10.1093/toxsci/kfq111.  Missing or empty |title= (help)
  30. ^ Traynelis, Stephen; Cull-Candy (May 24, 1990). "Stuart". Nature 345 (6273): 347-50. PMID 1692970. doi:10.1038/345347a0. 
  31. ^ Aizenman E, Lipton SA, Loring RH (March 1989). "Selective modulation of NMDA responses by reduction and oxidation". Neuron 2 (3): 1257–63. PMID 2696504. doi:10.1016/0896-6273(89)90310-3. 
  32. ^ Yu XM, Askalan R, Keil GJ, Salter MW (January 1997). "NMDA channel regulation by channel-associated protein tyrosine kinase Src". Science 275 (5300): 674–8. PMID 9005855. doi:10.1126/science.275.5300.674. 
  33. ^ Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J (September 2005). "Reelin modulates NMDA receptor activity in cortical neurons". J. Neurosci. 25 (36): 8209–16. PMID 16148228. doi:10.1523/JNEUROSCI.1951-05.2005. 
  34. ^ Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (July 2007). "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation". Nat. Neurosci. 10 (7): 880–6. PMID 17529984. doi:10.1038/nn1914. 
  35. ^ Zhang S, Edelmann L, Liu J, Crandall JE, Morabito MA (January 2008). "Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors". J. Neurosci. 28 (2): 415–24. PMID 18184784. doi:10.1523/JNEUROSCI.1900-07.2008. 
  36. ^ a b Fourgeaud L, Davenport CM, Tyler CM, Cheng TT, Spencer MB, Boulanger LM (December 2010). "MHC class I modulates NMDA receptor function and AMPA receptor trafficking". Proc Natl Acad Sci U S A 107 (51): 22278–83. PMC 3009822. PMID 21135233. doi:10.1073/pnas.0914064107. 
  37. ^ Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ (December 2000). "Functional requirement for class I MHC in CNS development and plasticity". Science 290 (5499): 2155–9. PMC 2175035. PMID 11118151. doi:10.1126/science.290.5499.2155. 
  38. ^ Nelson, PA; Sage, JR; Wood, SC; Davenport, CM; Anagnostaras, SG; Boulanger, LM (Sep 1, 2013). "MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression.". Learning & memory (Cold Spring Harbor, N.Y.) 20 (9): 505–17. PMID 23959708. doi:10.1101/lm.031351.113. 
  39. ^ Purves, Dale; George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, Leonard E. White (2008). Neuroscience, 4th Ed. Sinauer Associates. pp. 129–131. ISBN 978-0-87893-697-7. 
  40. ^ Purves, Dale; George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, Leonard E. White (2008). Neuroscience, 4th Ed. Sinauer Associates. pp. 191–195. ISBN 978-0-87893-697-7. 
  41. ^ Mount C, Downton C (July 2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. PMID 16829947. doi:10.1038/nm0706-780. 
  42. ^ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
  43. ^ Wijesinghe, R (2014). "Emerging Therapies for Treatment Resistant Depression". Ment Health Clin 4 (5): 56. ISSN 2168-9709. 
  44. ^ Linda Poon (2014). "Growing Evidence That A Party Drug Can Help Severe Depression". NPR. 
  45. ^ Gary Stix (2014). "From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment". Scientific American. 
  46. ^ Lisman JE, Coyle JT, Green RW et al. (May 2008). "Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia". Trends in Neurosciences 31 (5): 234–42. PMC 2680493. PMID 18395805. doi:10.1016/j.tins.2008.02.005. 
  47. ^ Liu XB, Murray KD, Jones EG (October 2004). "Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development". J. Neurosci. 24 (40): 8885–95. PMID 15470155. doi:10.1523/JNEUROSCI.2476-04.2004.