Skip to main content
SpringerLink
Log in

Neuropathological Background of MK-801 for Inducing Murine Model of Schizophrenia

  • Chapter
  • First Online:
Psychiatry and Neuroscience Update - Vol. II

Abstract

Schizophrenia is a complex psychiatric disorder with a developmental component that compromises neural circuits. Understanding the neuropathological basis of schizophrenia remains a major challenge for establishing new therapeutic approaches. In this review, causal factors for abnormal brain development in schizophrenia are discussed, with particular focus on N-methyl-D-aspartate (NMDA) receptor hypofunction and GABAergic circuit-mediated neurotransmission. Changes in interneuron structure and function have been reported in schizophrenia, and current evidence points to a specific involvement of interneuronal NMDA receptor signaling. Furthermore, altered gamma-band oscillations in schizophrenic patients drew attention to a possible deficit in fast-spiking parvalbumin-expressing interneurons, which play an essential role in regulating complex interaction between pyramidal cells, and represent a key to the understanding of network operations. Here, we describe the major biochemical, neuropathological, and cognitive deficits present in schizophrenic human individuals, and the faithfulness of animal models for mimicking those impairments. In NMDA receptor antagonism-based animal models, repeated injections of MK-801 (dizocilpine) during early postnatal brain development, disrupt the excitation/inhibition balance. A unifying hypothesis to explain the altered brain function in this model is a specific perturbation of GABAergic cells that results in long-term structural brain changes and modified network activity in adulthood, especially when MK-801 is administered during neurodevelopment. Subsequent impairment in cognition, particularly working memory and associative memory, are extremely relevant for schizophrenia research.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5):e141.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull. 2000;26(1):119–36.

    Article  CAS  PubMed  Google Scholar 

  3. Gold JM. Cognitive deficits as treatment targets in schizophrenia. Schizophr Res. 2004;72(1):21–8.

    Article  PubMed  Google Scholar 

  4. Bouwmans C, de Sonneville C, Mulder CL, Hakkaart-van RL. Employment and the associated impact on quality of life in people diagnosed with schizophrenia. Neuropsychiatr Dis Treat. 2015;11:2125–42.

    PubMed  PubMed Central  Google Scholar 

  5. Bergen SE, Petryshen TL. Genome-wide association studies of schizophrenia: does bigger lead to better results? Curr Opin Psychiatry. 2012;25(2):76–82.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kukshal P, Thelma BK, Nimgaonkar VL, Deshpande SN. Genetics of schizophrenia from a clinicial perspective. Int Rev Psychiatry. 2012;24(5):393–404.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Owen MJ. Implications of genetic findings for understanding schizophrenia. Schizophr Bull. 2012;38(5):904–7.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Greenwood TA, Swerdlow NR, Gur RE, Cadenhead KS, Calkins ME, Dobie DJ, et al. Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia. Am J Psychiatry. 2013;170(5):521–32.

    Article  PubMed  Google Scholar 

  9. Singh S, Kumar A, Agarwal S, Phadke SR, Jaiswal Y. Genetic insight of schizophrenia: past and future perspectives. Gene. 2014;535(2):97–100.

    Article  CAS  PubMed  Google Scholar 

  10. Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev Neurobiol. 2012;72(10):1272–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Labouesse MA, Langhans W, Meyer U. Long-term pathological consequences of prenatal infection: beyond brain disorders. Am J Physiol Regul Integr Comp Physiol. 2015;309(1):R1–R12.

    Article  CAS  PubMed  Google Scholar 

  12. Bourque F, van der Ven E, Fusar-Poli P, Malla A. Immigration, social environment and onset of psychotic disorders. Curr Pharm Des. 2012;18(4):518–26.

    Article  CAS  PubMed  Google Scholar 

  13. Pishva E, Kenis G, van den Hove D, Lesch KP, Boks MP, van Os J, et al. The epigenome and postnatal environmental influences in psychotic disorders. Soc Psychiatry Psychiatr Epidemiol. 2014;49(3):337–48.

    Article  PubMed  Google Scholar 

  14. Uher R. Gene–environment interactions in severe mental illness. Front Psych. 2014;5:48.

    Google Scholar 

  15. Ordóñez AE, Luscher ZI, Gogtay N. Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings. Schizophr Res. 2015;72(8):803–12.

    Google Scholar 

  16. Kubota M, van Haren NE, Haijma SV, Schnack HG, Cahn W, Hulshoff Pol HE et al. Association of IQ changes and progressive brain changes in patients with schizophrenia. JAMA Psychiatry. 2015;72(8):​803–12.

    Google Scholar 

  17. Garey L. When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits. J Anat. 2010;217(4):324–33.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu J, Corbera S, Wexler BE. Neural activation abnormalities during self-referential processing in schizophrenia: an fMRI study. Psychiatry Res. 2014;222(3):165–71.

    Article  PubMed  Google Scholar 

  19. Silver H, Feldman P, Bilker W, Gur RC. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am J Psychiatry. 2003;160(10):1809–16.

    Article  PubMed  Google Scholar 

  20. Barch DM. What can research on schizophrenia tell us about the cognitive neuroscience of working memory? Neuroscience. 2006;139(1):73–84.

    Article  CAS  PubMed  Google Scholar 

  21. Wolf DH, Satterthwaite TD, Calkins ME, Ruparel K, Elliott MA, Hopson RD. Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms. JAMA Psychiat. 2015;72(5):456–65.

    Article  Google Scholar 

  22. Brunoni AR, Vanderhasselt MA. Working memory improvement with non-invasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-analysis. Brain Cogn. 2014;86:1–9.

    Google Scholar 

  23. Arnsten AF, Jin LE. Molecular influences on working memory circuits in dorsolateral prefrontal cortex. Prog Mol Biol Transl Sci. 2014;122:211–31.

    Article  CAS  PubMed  Google Scholar 

  24. Benes FM. Emerging principles of altered neural circuitry in schizophrenia. Brain Res Brain Res Rev. 2000;31(2-3):251–69.

    Article  CAS  PubMed  Google Scholar 

  25. Rotaru DC, Lewis DA, Gonzalez-Burgos G. The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia. Rev Neurosci. 2012;23(1):97–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Volk DW, Lewis DA. Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction. Physiol Behav. 2002;77(4-5):501–5.

    Article  CAS  PubMed  Google Scholar 

  27. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, et al. Regionally specific disturbance of dorsolateral prefrontal–hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry. 2005;62(4):379–86.

    Article  PubMed  Google Scholar 

  28. Godsil BP, Kiss JP, Spedding M, Jay TM. The hippocampal–prefrontal pathway: the weak link in psychiatric disorders? Eur Neuropsychopharmacol. 2013;23(10):1165–81.

    Article  CAS  PubMed  Google Scholar 

  29. Blot K, Bai J, Otani S. The effect of non-competitive NMDA receptor antagonist MK-801 on neuronal activity in rodent prefrontal cortex: an animal model for cognitive symptoms of schizophrenia. J Physiol Paris. 2013;107(6):448–51.

    Article  PubMed  Google Scholar 

  30. Blum BP, Mann JJ. The GABAergic system in schizophrenia. Int J Neuropsychopharmacol. 2002;5(2):159–79.

    Article  CAS  PubMed  Google Scholar 

  31. Reynolds GP, Abdul-Monim Z, Neill JC, Zhang ZJ. Calcium binding protein markers of GABA deficits in schizophrenia — postmortem studies and animal models. Neurotox Res. 2004;6(1):57–61.

    Article  PubMed  Google Scholar 

  32. Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015;77(12):1031–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Joshi D, Catts VS, Olaya JC, Shannon WC. Relationship between somatostatin and death receptor expression in the orbital frontal cortex in schizophrenia: a postmortem brain mRNA study. NPJ Schizophrenia. 2015;1:14004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jentsch TJ, Stein V, Weinreich F, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev. 2002;82(2):503–68.

    Article  CAS  PubMed  Google Scholar 

  35. Le Magueresse C, Monyer H. GABAergic interneurons shape the functional maturation of the cortex. Neuron. 2013;77(3):388–405.

    Article  CAS  PubMed  Google Scholar 

  36. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry. 2000;57(3):237–45.

    Article  CAS  PubMed  Google Scholar 

  37. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23(15):6315–26.

    CAS  PubMed  Google Scholar 

  38. Zhang ZJ, Reynolds GP. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res. 2002;55(1–2):1–10.

    Article  PubMed  Google Scholar 

  39. Singer W. The formation of cooperative cell assemblies in the visual cortex. J Exp Biol. 1990;153:177–97.

    CAS  PubMed  Google Scholar 

  40. Uhlhaas PJ. Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia. Curr Opin Neurobiol. 2013;23(2):283–90.

    Article  CAS  PubMed  Google Scholar 

  41. Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. 2012;62(3):1574–83.

    Article  CAS  PubMed  Google Scholar 

  42. Williams S, Boksa P. Gamma oscillations and schizophrenia. J Psychiatry Neurosci. 2010;35(2):75–7.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Qin ZH, Zhang SP, Weiss B. Dopaminergic and glutamatergic blocking drugs differentially regulate glutamic acid decarboxylase mRNA in mouse brain. Brain Res Mol Brain Res. 1994;21(3-4):293–302.

    Article  CAS  PubMed  Google Scholar 

  44. Gierdalski M, Jablonska B, Smith A, Skangiel-Kramska J, Kossut M. Deafferentation induced changes in GAD67 and GluR2 mRNA expression in mouse somatosensory cortex. Brain Res Mol Brain Res. 1999;71(1):111–9.

    Article  CAS  PubMed  Google Scholar 

  45. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397(6716):251–5.

    Article  CAS  PubMed  Google Scholar 

  46. Bortone D, Polleux F. KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron. 2009;62(1):53–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Del Rio JA, Soriano E, Ferrer I. Development of GABA-immunoreactivity in the neocortex of the mouse. J Comp Neurol. 1992;326(4):501–26.

    Article  CAS  PubMed  Google Scholar 

  48. Doischer D, Hosp JA, Yanagawa Y, Obata K, Jonas P, Vida I, et al. Postnatal differentiation of basket cells from slow to fast signaling devices. J Neurosci. 2008;28(48):12956–68.

    Article  CAS  PubMed  Google Scholar 

  49. Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci. 1992;12(11):4151–72.

    CAS  PubMed  Google Scholar 

  50. Fritschy JM, Meskenaite V, Weinmann O, Honer M, Benke D, Mohler H. GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. Eur J Neurosci. 1999;11(3):761–8.

    Article  CAS  PubMed  Google Scholar 

  51. Bitanihirwe BK, Woo TU. Perineuronal nets and schizophrenia: the importance of neuronal coatings. Neurosci Biobehav Rev. 2014;45:85–99.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Eastwood SL, Harrison PJ. Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol Psychiatry. 2003;8(9):769. 821–31

    Article  CAS  PubMed  Google Scholar 

  53. Joshi D, Fung SJ, Rothwell A, Weickert CS. Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia. Biol Psychiatry. 2012;72(9):725–33.

    Article  CAS  PubMed  Google Scholar 

  54. Steinecke A, Gampe C, Valkova C, Kaether C, Bolz J. Disrupted-in-schizophrenia 1 (DISC1) is necessary for the correct migration of cortical interneurons. J Neurosci. 2012;32(2):738–45.

    Article  CAS  PubMed  Google Scholar 

  55. Fazzari P, Paternain AV, Valiente M, Pla R, Luján R, Lloyd K, et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010;464(7293):1376–80.

    Article  CAS  PubMed  Google Scholar 

  56. Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex. 2002;12(10):1063–70.

    Article  PubMed  Google Scholar 

  57. Zheng K, An JJ, Yang F, Xu W, Xu ZQ, Wu J, et al. TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus. Proc Natl Acad Sci U S A. 2011;108(41):17201–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 2000;23(3):223–39.

    Article  CAS  PubMed  Google Scholar 

  59. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13(10):1161–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rujescu D, Bender A, Keck M, Hartmann AM, Ohl F, Raeder H, et al. A pharmacological model for psychosis based on N-methyl-D-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities. Biol Psychiatry. 2006;59(8):721–9.

    Article  CAS  PubMed  Google Scholar 

  61. Abekawa T, Ito K, Nakagawa S, Koyama T. Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine. Psychopharmacology (Berl). 2007;192(3):303–16.

    Article  CAS  Google Scholar 

  62. Braun I, Genius J, Grunze H, Bender A, Möller HJ, Rujescu D. Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism. Schizophr Res. 2007;97(1–3):254–63.

    Article  PubMed  Google Scholar 

  63. Coleman Jr LG, Jarskog LF, Moy SS, Crews FT. Deficits in adult prefrontal cortex neurons and behavior following early post-natal NMDA antagonist treatment. Pharmacol Biochem Behav. 2009;93(3):322–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li JT, Zhao YY, Wang HL, Wang XD, Su YA, Si TM. Long-term effects of neonatal exposure to MK-801 on recognition memory and excitatory-inhibitory balance in rat hippocampus. Neuroscience. 2015;308:134–43.

    Article  CAS  PubMed  Google Scholar 

  65. Marcotte ER, Pearson DM, Srivastava LK. Animal models of schizophrenia: a critical review. J Psychiatry Neurosci. 2001;26(5):395–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jones CA, Watson DJG, Fone KCF. Animal models of schizophrenia. Br J Pharmacol. 2011;164(4):1162–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. van der Staay FJ, Arndt SS, Nordquist RE. Evaluation of animal models of neurobehavioral disorders. Behav Brain Funct. 2009;5:11.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Salgado JV, Sandner G. A critical overview of animal models of psychiatric disorders: challenges and perspectives. Rev Bras Psiquiatr. 2013;35(Suppl 2):S77–81.

    Article  PubMed  Google Scholar 

  69. Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev. 2008;32(5):1014–23.

    Article  PubMed  CAS  Google Scholar 

  70. Jones GH, Hernandez TD, Kendall DA, Marsden CA, Robbins TW. Dopaminergic and serotonergic function following isolation rearing in rats: study of behavioural responses and postmortem and in vivo neurochemistry. Pharmacol Biochem Behav. 1992;43(1):17–35.

    Article  CAS  PubMed  Google Scholar 

  71. Geyer MA, Wilkinson LS, Humby T, Robbins TW. Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol Psychiatry. 1993;34(6):361–72.

    Article  CAS  PubMed  Google Scholar 

  72. Wilkinson LS, Killcross SS, Humby T, Hall FS, Geyer MA, Robbins TW. Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition. Neuropsychopharmacology. 1994;10(1):61–72.

    Article  CAS  PubMed  Google Scholar 

  73. Gilabert-Juan J, Belles M, Saez AR, Carceller H, Zamarbide-Fores S, Moltó MD, et al. A “double hit” murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus. Neurobiol Dis. 2013;59:126–40.

    Article  CAS  PubMed  Google Scholar 

  74. Daenen EW, Wolterink G, Van Der Heyden JA, Kruse CG, Van Ree JM. Neonatal lesions in the amygdala or ventral hippocampus disrupt prepulse inhibition of the acoustic startle response; implications for an animal model of neurodevelopmental disorders like schizophrenia. Eur Neuropsychopharmacol. 2003;13(3):187–97.

    Article  CAS  PubMed  Google Scholar 

  75. Rueter LE, Ballard ME, Gallagher KB, Basso AM, Curzon P, Kohlhaas KL. Chronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia. Psychopharmacology (Berl). 2004;176(3–4):312–9.

    Article  CAS  Google Scholar 

  76. Marquis JP, Goulet S, Doré FY. Neonatal ventral hippocampus lesions disrupt extra-dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats. Neurobiol Learn Mem. 2008;90(2):339–46.

    Article  PubMed  Google Scholar 

  77. Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, et al. A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J Neurosci. 2008;28(48):12691–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry. 2010;67(2):113–23.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Grace AA. Gating of information flow within the limbic system and the. Brain Res Brain Res Rev. 2000;31(2–3):330–41.

    Article  CAS  PubMed  Google Scholar 

  80. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25(4):455–67.

    Article  CAS  PubMed  Google Scholar 

  81. Grüter T, Wiescholleck V, Dubovyk V, Aliane V, Manahan-Vaughan D. Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis. Front Behav Neurosci. 2015;9:117.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Lim AL, Taylor DA, Malone DT. Consequences of early life MK-801 administration: long-term behavioural effects and relevance to schizophrenia research. Behav Brain Res. 2012;227(1):276–86.

    Article  CAS  PubMed  Google Scholar 

  83. Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986;83(18):7104–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Snyder MA, Gao WJ. NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front Cell Neurosci. 2013;7:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated ‘ménage à trois’. Trends Neurosci. 1997;20(11):523–9.

    Article  CAS  PubMed  Google Scholar 

  86. Newcomer JW, Farber NB, Olney JW. NMDA receptor function, memory, and brain aging. Dialogues Clin Neurosci. 2000;2(3):219–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12(3):529–40.

    Article  CAS  PubMed  Google Scholar 

  88. Soria JM, Valdeolmillos M. Receptor-activated calcium signals in tangentially migrating cortical cells. Cereb Cortex. 2002;12(8):831–9.

    Article  CAS  PubMed  Google Scholar 

  89. Wang HX, Gao WJ. Cell type-specific development of NMDA receptors in the interneurons of rat prefrontal cortex. Neuropsychopharmacology. 2009;34(8):2028–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang H, Stradtman 3rd GG, Wang XJ, Gao WJ. A specialized NMDA receptor function in layer 5 recurrent microcircuitry of the adult rat prefrontal cortex. Proc Natl Acad Sci U S A. 2008;105(43):16791–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24(4):417–63.

    Article  CAS  PubMed  Google Scholar 

  92. Roberts AC, Díez-García J, Rodriguiz RM, López IP, Luján R, Martínez-Turrillas R, et al. Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron. 2009;63(3):342–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci. 2010;30(13):4590–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gambrill AC, Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A. 2011;108(14):5855–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron. 2011;71(6):1085–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Moghaddam B. Bringing order to the glutamate chaos in schizophrenia. Neuron. 2003;40(5):881–4.

    Article  CAS  PubMed  Google Scholar 

  97. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40–68.

    Article  CAS  PubMed  Google Scholar 

  98. Morris BJ, Cochran SM, Pratt JA. PCP: from pharmacology to modelling schizophrenia. Curr Opin Pharmacol. 2005;5(1):101–6.

    Article  CAS  PubMed  Google Scholar 

  99. Lewis DA, Gonzalez-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology. 2008;33:141–65.

    Article  PubMed  Google Scholar 

  100. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–4.

    Article  CAS  PubMed  Google Scholar 

  101. Cotter DR, Pariante CM, Everall IP. Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull. 2001;55(5):585–95.

    Article  CAS  PubMed  Google Scholar 

  102. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U. How do glial–neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia? Neurochem Int. 2007;50(2):291–301.

    Article  CAS  PubMed  Google Scholar 

  103. Kondziella D, Brenner E, Eyjolfsson EM, Markinhuhta KR, Carlsson ML, Sonnewald U. Glial–neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. Neuropsychopharmacology. 2006;31(9):1880–7.

    Article  CAS  PubMed  Google Scholar 

  104. Ringler S, Aye J, Byrne E, Anderson M, Turner C. Effects of disrupting calcium homeostasis on neuronal maturation: early inhibition and later recovery. Cell Mol Neurobiol. 2008;28(3):389–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, et al. NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci. 1996;16(6):2034–43.

    CAS  PubMed  Google Scholar 

  106. van der Staay FJ, Rutten K, Erb C, Blokland A. Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav Brain Res. 2011;220(1):215–29.

    Article  PubMed  CAS  Google Scholar 

  107. Wang HX, Gao WJ. Prolonged exposure to NMDAR antagonist induces cell-type specific changes of glutamatergic receptors in rat prefrontal cortex. Neuropharmacology. 2012;62(4):1808–22.

    Article  CAS  PubMed  Google Scholar 

  108. Takahashi N, Sakurai T. Roles of glial cells in schizophrenia: possible targets for therapeutic approaches. Neurobiol Dis. 2013;53:49–60.

    Article  CAS  PubMed  Google Scholar 

  109. Matute C, Melone M, Vallejo-Illarramendi A, Conti F. Increased expression of the astrocytic glutamate transporter GLT-1 in the prefrontal cortex of schizophrenics. Glia. 2005;49(3):451–5.

    Article  PubMed  Google Scholar 

  110. Simpson MD, Slater P, Deakin JF. Comparison of glutamate and gamma-aminobutyric acid uptake binding sites in frontal and temporal lobes in schizophrenia. Biol Psychiatry. 1998;44(6):423–7.

    Article  CAS  PubMed  Google Scholar 

  111. Fattorini G, Melone M, Bragina L, Candiracci C, Cozzi A, Pellegrini Giampietro DE, et al. GLT-1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine. Glia. 2008;56(12):1320–7.

    Article  PubMed  Google Scholar 

  112. Matos M, Augusto E, Santos-Rodrigues AD, Schwarzschild MA, Chen JF, Cunha RA, et al. Adenosine A2A receptors modulate glutamate uptake in cultured astrocytes and gliosomes. Glia. 2012;60(5):702–16.

    Article  PubMed  Google Scholar 

  113. Matos M, Shen HY, Augusto E, Wang Y, Wei CJ, Wang YT, et al. Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biol Psychiatry. 2015;78(11):763–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Harada K, Nakato K, Yarimizu J, Yamazaki M, Morita M, Takahashi S, et al. A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535. Eur J Pharmacol. 2012;685(1–3):59–69.

    Article  CAS  PubMed  Google Scholar 

  115. Shimazaki T, Kaku A, Chaki S. D-Serine and a glycine transporter-1 inhibitor enhance social memory in rats. Psychopharmacology (Berl). 2010;209(3):263–70.

    Article  CAS  Google Scholar 

  116. Black MD, Varty GB, Arad M, Barak S, De Levie A, Boulay D, et al. Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat. Psychopharmacology (Berl). 2009;202(1–3):385–96.

    Article  CAS  Google Scholar 

  117. Manahan-Vaughan D, Wildförster V, Thomsen C. Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter-1 (GlyT1). Eur J Neurosci. 2008;28(7):1342–50.

    Article  PubMed  Google Scholar 

  118. Karasawa J, Hashimoto K, Chaki S. D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res. 2008;186(1):78–83.

    Article  CAS  PubMed  Google Scholar 

  119. Jodo E, Suzuki Y, Katayama T, Hoshino KY, Takeuchi S, Niwa S, et al. Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo–prefrontal pathway. Cereb Cortex. 2005;15(5):663–9.

    Article  PubMed  Google Scholar 

  120. Wang GW, Cai JX. Disconnection of the hippocampal–prefrontal cortical circuits impairs spatial working memory performance in rats. Behav Brain Res. 2006;175(2):329–36.

    Article  PubMed  Google Scholar 

  121. Wang GW, Cai JX. Reversible disconnection of the hippocampal–prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats. Neurobiol Learn Mem. 2008;90(2):365–73.

    Article  CAS  PubMed  Google Scholar 

  122. Churchwell JC, Kesner RP. Hippocampal–prefrontal dynamics in spatial working memory: interactions and independent parallel processing. Behav Brain Res. 2011;225(2):389–95.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Hasan A, Nitsche MA, Rein B, Schneider-Axmann T, Guse B, Gruber O, et al. Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation. Behav Brain Res. 2011;224(1):15–22.

    Article  PubMed  Google Scholar 

  124. Gargiulo PA, Siemann M, Delius JD. Visual discrimination in pigeons impaired by glutamatergic blockade of nucleus accumbens. Physiol Behav. 1998;63(4):705–9.

    Article  CAS  PubMed  Google Scholar 

  125. Gargiulo PA, Acerbo MJ, Krug I, Delius JD. Cognitive effects of dopaminergic and glutamatergic blockade in nucleus accumbens in pigeons. Pharmacol Biochem Behav. 2005;81(4):732–9.

    Article  CAS  PubMed  Google Scholar 

  126. Gargiulo PA, Landa De Gargiulo AI. Glutamate and modeling of schizophrenia symptoms: review of our findings: 1990–2014. Pharmacol Rep. 2014;66(3):343–52.

    Article  CAS  PubMed  Google Scholar 

  127. Baiardi G, Ruiz AM, Beling A, Borgonovo J, Martínez G, Landa AI, et al. Glutamatergic ionotropic blockade within accumbens disrupts working memory and might alter the endocytic machinery in rat accumbens and prefrontal cortex. J Neural Transm (Vienna). 2007;114(12):1519–28.

    Article  CAS  Google Scholar 

  128. Pause BM, Zlomuzica A, Kinugawa K, Mariani J, Pietrowsky R, Dere E. Perspectives on episodic-like and episodic memory. Front Behav Neurosci. 2013;7:33.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Dudchenko PA. An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev. 2004;28(7):699–709.

    Article  PubMed  Google Scholar 

  130. Li JT, Su YA, Guo CM, Feng Y, Yang Y, Huang RH, Si TM. Persisting cognitive deficits induced by low-dose, subchronic treatment with MK-801 in adolescent rats. Eur J Pharmacol. 2011;652(1–3):65–72.

    Article  CAS  PubMed  Google Scholar 

  131. Zemanova A, Stankova A, Lobellova V, Svoboda J, Vales K, Vlcek K, et al. Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: an effect of pretraining. Pharmacol Biochem Behav. 2013;106:117–23.

    Article  CAS  PubMed  Google Scholar 

  132. Su YA, Huang RH, Wang XD, Li JT, Si TM. Impaired working memory by repeated neonatal MK-801 treatment is ameliorated by galantamine in adult rats. Eur J Pharmacol. 2014;725:32–9.

    Article  CAS  PubMed  Google Scholar 

  133. Kim TW, Kang HS, Park JK, Lee SJ, Baek SB, Kim CJ. Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice. Mol Med Rep. 2014;10(6):2924–30.

    CAS  PubMed  Google Scholar 

  134. Li ML, Yang SS, Xing B, Ferguson BR, Gulchina Y, Li YC, et al. LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment. Exp Neurol. 2015;273:190–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Stuchlik A, Rezacova L, Vales K, Bubenikova V, Kubik S. Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze. Neurosci Lett. 2004;366(2):162–6.

    Article  CAS  PubMed  Google Scholar 

  136. Lobellova V, Entlerova M, Svojanovska B, Hatalova H, Prokopova I, Petrasek T, et al. Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose–response study. Behav Brain Res. 2013;246:55–62.

    Article  CAS  PubMed  Google Scholar 

  137. Vales K, Bubenikova-Valesova V, Klement D, Stuchlik A. Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long–Evans and Wistar rats. Neurosci Res. 2006;55(4):383–8.

    Article  CAS  PubMed  Google Scholar 

  138. Singer P, Hauser J, Llano Lopez L, Peleg-Raibstein D, Feldon J, Gargiulo PA, Yee BK. Prepulse inhibition predicts working memory performance whilst startle habituation predicts spatial reference memory retention in C57BL/6 mice. Behav Brain Res. 2013;242:166–77.

    Article  PubMed  Google Scholar 

  139. Nozari M, Mansouri FA, Shabani M, Nozari H, Atapour N. Postnatal MK-801 treatment of female rats impairs acquisition of working memory, but not reference memory in an eight-arm radial maze; no beneficial effects of enriched environment. Psychopharmacology (Berl). 2015;232(14):2541–50.

    Article  CAS  Google Scholar 

  140. Hanlon FM, Weisend MP, Hamilton DA, Jones AP, Thoma RJ, Huang M, et al. Impairment on the hippocampal-dependent virtual Morris water task in schizophrenia. Schizophr Res. 2006;87(1–3):67–80.

    Article  PubMed  Google Scholar 

  141. Han K, Young Kim I, Kim JJ. Assessment of cognitive flexibility in real life using virtual reality: a comparison of healthy individuals and schizophrenia patients. Comput Biol Med. 2012;42(8):841–7.

    Article  PubMed  Google Scholar 

  142. Ferino F, Thierry AM, Glowinski J. Anatomical and electrophysiological evidence for a direct projection from Ammon’s horn to the medial prefrontal cortex in the rat. Exp Brain Res. 1987;65(2):421–6.

    Article  CAS  PubMed  Google Scholar 

  143. Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA. Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther. 2009;122(2):150–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Dere E, Huston JP, De Souza Silva MA. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev. 2007;31(5):673–704.

    Article  CAS  PubMed  Google Scholar 

  145. Lyon L, Saksida LM, Bussey TJ. Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models. Psychopharmacology (Berl). 2012;220(4):647–72.

    Article  CAS  Google Scholar 

  146. King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation — an effect sensitive to NMDA receptor antagonism. Neuropharmacology. 2004;47(2):195–204.

    Article  CAS  PubMed  Google Scholar 

  147. Nilsson M, Hansson S, Carlsson A, Carlsson ML. Differential effects of the N-methyl-d-aspartate receptor antagonist MK-801 on different stages of object recognition memory in mice. Neuroscience. 2007;149(1):123–30.

    Article  CAS  PubMed  Google Scholar 

  148. Lim AL, Taylor DA, Malone DT. A two-hit model: behavioural investigation of the effect of combined neonatal MK-801 administration and isolation rearing in the rat. J Psychopharmacol. 2012;26(9):1252–64.

    Article  CAS  PubMed  Google Scholar 

  149. Stefani MR, Moghaddam B. Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry. 2005;57(4):433–6.

    Article  CAS  PubMed  Google Scholar 

  150. Baier PC, Blume A, Koch J, Marx A, Fritzer G, Aldenhoff JB, Schiffelholz T. Early postnatal depletion of NMDA receptor development affects behaviour and NMDA receptor expression until later adulthood in rats — a possible model for schizophrenia. Behav Brain Res. 2009;205(1):96–101.

    Article  CAS  PubMed  Google Scholar 

  151. Achim AM, Lepage M. Is associative recognition more impaired than item recognition memory in schizophrenia? Brain and Cogn. 2003;53:121–4.

    Article  Google Scholar 

  152. Danion JM, Huron C, Vidailhet P, Berna F. Functional mechanisms of episodic memory impairment in schizophrenia. Can J Psychiatry. 2007;52:693–701.

    Article  PubMed  Google Scholar 

  153. Winters BD, Bussey TJ. Glutamate receptors in perirhinal cortex mediate encoding, retrieval, and consolidation of object recognition memory. J Neurosci. 2005;25(17):4243–51.

    Article  CAS  PubMed  Google Scholar 

  154. Barker GRI, Warburton EC. Object-in-place associative recognition memory depends on glutamate receptor neurotransmission within two defined hippocampal–cortical circuits: a critical role for AMPA and NMDA receptors in the hippocampus, perirhinal, and prefrontal cortices. Cereb Cortex. 2015;25(2):472–81.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the University of the Basque Country UPV/EHU (UFI 11/32), (EHU 14/33), and by the Government of the Basque Country (GIC IT 901/16). Murueta-Goyena A is financed by a predoctoral fellowship of the University of the Basque Country (UPV/EHU).

Author information

Authors and Affiliations

  1. Laboratory of Clinical and Experimental Neurosicence (LaNCE), Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain

    Ane Murueta-Goyena Larrañaga MSc, Arkaitz Bengoetxea Odrioizola & José Vicente Lafuente Sánchez

  2. University of the Basque Country, Laboratory of Clinical and Experimental Neuroscience, Department of Neuroscience, Faculty of Medicine and Nursing, Barrio Sarriena s/n, Leioa, Bizkaia, 48940, Spain

    Ane Murueta-Goyena Larrañaga MSc

  3. Laboratory of Neurosciences and Experimental Psychology, CONICET, Area of Pharmacology, Department of Pathology, Faculty of Medical Sciences, National University of Cuyo, Mendoza, Argentina

    Pascual Ángel Gargiulo

Authors
  1. Ane Murueta-Goyena Larrañaga MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arkaitz Bengoetxea Odrioizola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pascual Ángel Gargiulo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José Vicente Lafuente Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ane Murueta-Goyena Larrañaga MSc .

Editor information

Editors and Affiliations

  1. National University of Cuyo, Catholic University of Argentina, Guaymallen Mendoza, Argentina

    Pascual Ángel Gargiulo

  2. Institute of Neurobiology Foundation, National Academy of Medicine, Buenos Aires, Argentina

    Humberto Luis Mesones-Arroyo

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Murueta-Goyena Larrañaga, A., Odrioizola, A.B., Gargiulo, P.Á., Lafuente Sánchez, J.V. (2017). Neuropathological Background of MK-801 for Inducing Murine Model of Schizophrenia. In: Gargiulo, P., Mesones-Arroyo, H. (eds) Psychiatry and Neuroscience Update - Vol. II. Springer, Cham. https://doi.org/10.1007/978-3-319-53126-7_25

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-53126-7_25

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-53125-0

  • Online ISBN: 978-3-319-53126-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation