NMDA RECEPTORS, ANTI-NMDA RECEPTOR ANTIBODIES AND THEIR ROLE IN PSYCHIATRIC AND NEUROINFLAMMATORY DISORDERS

DOI: https://doi.org/10.29296/24999490-2021-01-01

O.V. Pavlova(1), K.A. Pavlov(1), A.A. Murashko(2), O.I. Gurina(1), A.B. Shmukler(2), 1-V. Serbsky National Medical Research Centre for Psychiatry and Narcology (V. Serbsky NMRCPN), Kropotkinsky bystreet, 23, Moscow, 119034, Russian Federation; 2-Moscow Research Institute of Psychiatry – the Branch of V. Serbsky National Medical Research Centre for Psychiatry and Narcology, Poteshnaya, 3, Moscow, 119034, Russian Federation E-mail: [email protected]

Little is known about the etiology of neuropsychiatric disorders. Glutamate-mediated excitotoxicity is one of the main pathological mechanisms occurring in various types of acute and chronic diseases of the central nervous system. Glutamate is the major excitatory neurotransmitter in the central nervous system. Recently, it has become evident that not only glutamate excess can cause massive brain damage. Several types of anti-glutamate receptor antibodies were found in serum and cerebrospinal fluid of patients with various mental and neuroinflammatory disorders. These antibodies can lead to the death of neurons and impaired neuronal function inducing various pathological mechanisms in the central nervous system. The discovery of autoantibodies binding to NMDA receptors and causing neurological and psychiatric symptoms has led to the hypothesis that autoimmune mechanisms may underlie some cases of mental disorders. This paper reviews the pathological mechanisms of antibodies against NMDA receptors based on the disorder defined as anti-NMDA receptor encephalitis. Anti-NMDA receptor encephalitis is a synaptic autoimmune disorder in which IgG autoantibodies against the NR1 subunit of the NMDA receptors occur and trigger pathological processes, manifesting with psychiatric symptoms in particular. The research in other mental and neuroinflammatory disorders also showed the presence of anti-NMDAR antibodies in a small part of patients. But the role of antibodies against the NMDA receptors in the development of psychotic symptoms is not fully understood and requires further research. Studies in this area are extremely promising, opening up new opportunities for understanding the pathogenesis of this group of disorders and developing new diagnostic and therapeutic approaches.
Keywords: 
NMDA-receptors, autoantibodies, encephalitis, psychosis, neuroinflammatory diseases, NMDA
Список литературы: 
  1. Fessel W.J. Autoimmunity and mental illness. A preliminary report. 1962. Arch. Gen. Psychiatry 6, 320–3.
  2. Coyle J.T., 2012. NMDA receptor and schizophrenia: a brief history. Schizophr. Bull. 38, 920–6. DOI: 10.1093/schbul/sbs076.
  3. Morozova A., Zorkina Y., Pavlov K., Pavlova O., Storozheva Z., Zubkov E., Zakharova N., Karpenko O., Reznik A., C hekhonin V., Kostyuk G. Association of rs4680 COMT, rs6280 DRD3, and rs7322347 5HT2A With Clinical Features of Youth-Onset Schizophrenia. Front Psychiatry. 2019; 10: 830. DOI: 10.3389/fpsyt.2019.00830.
  4. Vitaliani R., Mason W., Ances B., Zwerdling T., Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol. 2005; 58: 594–604.
  5. Dalmau J., Tüzün E., Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007; 61 (1): 25–36.
  6. Kayser M.S., Dalmau J. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophrenia Research 176. 2016; 36–40. DOI: 10.1016/j.schres.2014.10.007.
  7. Meldrum B.S. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 2000; 130 (4S Suppl): 1007-15. DOI: 10.1093/jn/130.4.1007S.
  8. Platt S.R. The role of glutamate in central nervous system health and disease--a review. Vet J. 2007; 173 (2): 278–86. Epub 2005 Dec 22.
  9. Balazs R. Trophic effect of glutamate. Curr. Top. Med. Chem. 2006; 6: 961–8. DOI: 10.2174/156802606777323700
  10. Davydova O.N., Boldyrev A.A. Glutamatnye retseptory v kletkah nervnoj i immunnoj sistem. Annaly klinicheskoj i eksperimental'noj nevrologii. 2007; 1 (7). [Davydova O.N., Boldyrev A.A. Glutamate receptors in cells of the nervous and immune systems. Annals of clinical and experimental neurology. 2007; 1 (7) (in Russian)]
  11. Okubo Y., Iino M. Visualization of glutamate as a volume transmitter. J. Physiol. 2011; 589 (Pt 3): 481–8. DOI: 10.1113/jphysiol.2010.199539. Epub 2010 Nov 29.
  12. Dingledine R., Borges K., Bowie D., Traynelis S.F. The glutamate receptor ion channels. Pharmacol. Rev. 1999; 51: 7–61.
  13. Rosenmund C., Stern-Bach Y., Stevens C.F. The tetrameric structure of a glutamate receptor channel. Science. 1998; 280 (5369): 1596–9.
  14. Das S., Sasaki Y.F., Rothe T., Premkumar L.S., Takasu M., Crandall J.E., Dikkes P., Conner D.A., Rayudu P.V., Cheung W., Chen H.S., Lipton S.A., Nakanishi N. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature. 1998; 393 (6683): 377–81.
  15. Kew J.N., Kemp J.A. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005; 179 (1): 4–29.
  16. Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren’s syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor’s expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J. Neural Transm (Vienna). 2014; 121 (8): 1029–75. DOI: 10.1007/s00702-014-1193-3.
  17. Maragos W.F., Penney J.B., Young A.B. Anatomic correlation of NMDA and 3H-TCP-labeled receptors in rat brain. J. Neurosci. 1988; 8 (2): 493–501.
  18. Monaghan D.T., Cotman C.W. Distribution of N-methyl-D-aspartate-sensitive L-[3H]glutamate-binding sites in rat brain. J. Neurosci. 1985; 5 (11): 2909–19.
  19. McGinnity C.J., Koepp M.J., Hammers A., Riaño Barros D.A., Pressler R.M., Luthra S., Jones P.A., Trigg W., Micallef C., Symms M.R., Brooks D.J., Duncan J.S. NMDA receptor binding in focal epilepsies. J Neurol Neurosurg Psychiatry. 2015; 86 (10): 1150–7. DOI: 10.1136/jnnp-2014-309897.
  20. Wang R., Reddy P.H. Role of Glutamate and NMDA Receptors in Alzheimer’s Disease. J. Alzheimers Dis. 2017; 57 (4): 1041–8. DOI: 10.3233/JAD-160763.
  21. Balu D.T. The NMDA Receptor and Schizophrenia: From Pathophysiology to Treatment. Adv Pharmacol. 2016; 76: 351–82. DOI: 10.1016/bs.apha.2016.01.006.
  22. Labrie V., Roder J.C. The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci Biobehav Rev. 2010; 34 (3): 351–72. DOI: 10.1016/j.neubiorev.2009.08.002.
  23. Grant S.G. Synapse signalling complexes and networks: machines underlying cognition. Bioessays 2003; 25: 1229–35.
  24. Khodorov B. Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones. Prog. Biophys. Mol. Biol. 2004; 86: 279–351.
  25. Leopold A.V., Chernov K.G., Shemetov A.A., Verkhusha V.V. Neurotrophin receptor tyrosine kinases regulated with near-infrared light. Nat Commun. 2019; 10 (1): 1129. DOI: 10.1038/s41467-019-08988-3.
  26. Danysz W., Parsons C.G. Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol. Rev. 1998; 50: 597–664.
  27. Carroll R.C., Zukin R.S. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends. Neurosci. 2002; 25: 571–7.
  28. Kayser M.S., Dalmau J., Anti-NMDA Receptor Encephalitis in Psychiatry. Curr Psychiatry Rev. 2011;7 (3): 189–93.
  29. Dalmau J., Armangué T., Planagumà J., Radosevic M., Mannara F., Leypoldt F., Geis C., Lancaster E., Titulaer M.J., Rosenfeld M.R., Graus F. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019; 18 (11): 1045–57. DOI: 10.1016/S1474-4422(19)30244-3.
  30. Al-Diwani A., Handel A., Townsend L., Pollak T., Leite M.I., Harrison P.J., Lennox B.R., Okai D., Manohar S.G., Irani S.R. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. Lancet Psychiatry. 2019; 6 (3): 235–46. DOI: 10.1016/S2215-0366(19)30001-X.
  31. Kayser M.S., Titulaer M.J., Gresa-Arribas N., Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti–N-methyl-d-aspartate receptor encephalitis. JAMA Neurol. 2013; 70 (9): 1133–9.
  32. Sarkis R.A., Coffey M.J., Cooper J.J., Hassan I., Lennox B. Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review of Psychiatric Phenotypes and Management Considerations: A Report of the American Neuropsychiatric Association Committee on Research. J. Neuropsychiatry Clin. Neurosci. 2019; 31 (2): 137–42. DOI: 10.1176/appi.neuropsych.18010005.
  33. Lejuste F., Thomas L., Picard G., Desestret V., Ducray F., Rogemond V., Psimaras D., Antoine J.C., Delattre J.Y., Groc L., Leboyer M., Honnorat J. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016; 3 (5): e280. DOI: 10.1212/NXI.0000000000000280.
  34. Warren N., Siskind D., O’Gorman C. Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis. Acta Psychiatr Scand. 2018; 138 (5): 401–8. DOI: 10.1111/acps.12941.
  35. Staley E.M., Jamy R., Phan A.Q., Figge D.A., Pham H.P. N-Methyl-d-aspartate Receptor Antibody Encephalitis: A Concise Review of the Disorder, Diagnosis, and Management. ACS Chem Neurosci. 2019; 10 (1): 132–42. DOI: 10.1021/acschemneuro.8b00304.
  36. Varley J.A., Webb A.J.S., Balint B., Fung V.S.C., Sethi K.D., Tijssen M.A.J., Lynch T., Mohammad S.S., Britton F., Evans M., Hacohen Y., Lin J.P., Nardocci N., Granata T., Dale R.C., Lim M.J., Bhatia K.P., Lang A.E., Irani S.R. The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study. J Neurol Neurosurg Psychiatry. 2019; 90 (6): 724–6. DOI: 10.1136/jnnp-2018-318584.
  37. Graus F., Titulaer M.J., Balu R., Benseler S., Bien C.G., Cellucci T., Cortese I., Dale R.C., Gelfand J.M., Geschwind M., Glaser C.A., Honnorat J., Höftberger R., Iizuka T., Irani S.R., Lancaster E., Leypoldt F., Prüss H., Rae-Grant A., Reindl M., Rosenfeld M.R., Rostásy K., Saiz A., Venkatesan A., Vincent A., Wandinger K.P., Waters P., Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15 (4): 391–404. DOI: 10.1016/S1474-4422(15)00401-9.
  38. Hughes E.G., Peng X., Gleichman A.J., Lai M., Zhou L., Tsou R., Parsons T.D., Lynch D.R., Dalmau J., Balice-Gordon R.J. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 2010; 30 (17): 5866–75. DOI: 10.1523/JNEUROSCI.0167-10.
  39. Gresa-Arribas N., Titulaer M.J., Torrents A., Aguilar E., McCracken L., Leypoldt F., Gleichman A.J., Balice-Gordon R., Rosenfeld M.R., Lynch D., Graus F., Dalmau J. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014; 13 (2): 167–77. DOI: 10.1016/S1474-4422(13)70282-5.
  40. Moscato E.H., Peng X., Jain A., Parsons T.D., Dalmau J., Balice-Gordon R.J. Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014; 76 (1): 108–19. DOI: 10.1002/ana.24195.
  41. 41. Mikasova L., De Rossi P., Bouchet D., Georges F., Rogemond V., Didelot A., Meissirel C., Honnorat J., Groc L. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain. 2012; 135 (Pt 5): 1606–21. DOI: 10.1093/brain/aws092.
  42. Manto M., Dalmau J., Didelot A., Rogemond V., Honnorat J. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet J. Rare Dis. 2010; 5: 31. DOI: 10.1186/1750-1172-5-31.
  43. Lau A., Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 2010; 460 (2): 525–42. DOI: 10.1007/s00424-010-0809-1.
  44. Norris C.M., Blalock E.M., Thibault O., Brewer L.D., Clodfelter G.V., Porter N.M., Landfield P.W. Electrophysiological mechanisms of delayed excitotoxicity: positive feedback loop between NMDA receptor current and depolarization-mediated glutamate release. J. Neurophysiol. 2006; 96 (5): 2488–500. Epub 2006 Aug 16.
  45. Joseph C. Masdeu, Ana González-Pinto, Carlos Matute, Sonia Ruiz De Azúa, A. Palomino, Jose De Leon, Karen F. Berman, Josep Dalmau. Serum IgG Antibodies Against the NR1 Subunit of the NMDA Receptor Not Detected in Schizophrenia. Am J. Psychiatry. 2012; 169 (10): 1120–1. DOI: 10.1176/appi.ajp.2012.12050646.
  46. Rhoads J., Guirgis H., McKnight C., Duchemin A.M. Lack of anti-NMDA Receptor Autoantibodies in the Serum of Subjects With Schizophrenia. Schizophr Res. 2011; 129 (2–3): 213–4. DOI: 10.1016/j.schres.2010.12.018. Epub 2011 Feb 1.
  47. Michael S. Zandi, Sarosh R. Irani, Bethan Lang, Patrick Waters, Peter B. Jones, Peter McKenna, Alasdair J. Coles, Angela Vincent, Belinda R. Lennox. Disease-relevant Autoantibodies in First Episode Schizophrenia. J. Neurol. 2011; 258 (4): 686–8. DOI: 10.1007/s00415-010-5788-9. Epub 2010 Oct 26.
  48. Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Shuken Boku, Wakako Ito, Jun Tokunaga, Akane Mori, Yasuo Hishikawa, Tetsuo Shimizu, Seiji Nishino. Anti-NMDA-receptor Antibody Detected in Encephalitis, Schizophrenia, and Narcolepsy With Psychotic Features. BMC Psychiatry. 2012; 12: 37. DOI: 10.1186/1471-244X-12-37
  49. Johann Steiner , Martin Walter, Wenzel Glanz, Zoltán Sarnyai, Hans-Gert Bernstein, Stefan Vielhaber, Andrea Kästner, Martin Skalej, Wolfgang Jordan, Kolja Schiltz, Christine Klingbeil, Klaus-Peter Wandinger, Bernhard Bogerts, Winfried Stoecker. Increased Prevalence of Diverse N-methyl-D-aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N-methyl-D-aspartate Glutamate Receptor Encephalitis. JAMA Psychiatry. 2013; 70 (3): 271–8. DOI: 10.1001/2013.jamapsychiatry.86.
  50. 50. Faith Dickerson , Cassie Stallings, Crystal Vaughan, Andrea Origoni, Sunil Khushalani, Robert Yolken. Antibodies to the Glutamate Receptor in Mania. Bipolar Disord. 2012; 14 (5): 547–53. DOI: 10.1111/j.1399-5618.2012.01028.x. Epub 2012 Jun 6.