Enriched Environment Reverts Somatostatin Interneuron Loss in MK-801 Model of Schizophrenia

  • Ane Murueta-GoyenaEmail author
  • Naiara Ortuzar
  • José Vicente Lafuente
  • Harkaitz Bengoetxea


Dysregulation of the inhibitory drive has been proposed to be a central mechanism to explain symptoms and pathophysiological hallmarks in schizophrenia. A number of recent neuroanatomical studies suggest that certain types of inhibitory cells are deficient in schizophrenia, including somatostatin-immunoreactive interneurons (SST+). The present study sought to use stereological methods to investigate whether the number of SST+ interneurons decreased after repeated injections of NMDA receptor antagonist MK-801 (0.5 mg/kg) and to determine the effect of limited exposure to an enriched environment (EE) in adult life on this sub-population of inhibitory cells. Considering that somatostatin expression is highly dependent on neurotrophic support, we explored the changes in the relative expression of proteins related to brain-derived neurotrophic factor—tyrosine kinase B (BDNF-TrkB) signaling between the experimental groups. We observed that early-life MK-801 treatment significantly decreased the number of SST+ interneurons in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of adult Long Evans rats. Contrarily, short-term exposure to EE increased the number of SST+ interneurons in MK-801-injected animals, except in the CA1 region of the hippocampus, whereas this increase was not observed in vehicle-injected rats. We also found upregulated BDNF-TrkB signaling after EE that triggered an increase in the pERK/ERK ratio in mPFC and HPC, and the pAkt/Akt ratio in HPC. Thus, the present results support the notion that SST+ interneurons are markedly affected after early-life NMDAR blockade and that EE promotes SST+ interneuron expression, which is partly mediated through the BDNF-TrkB signaling pathway. These results may have important implications for schizophrenia, as SST+ interneuron loss is also observed in the MK-801 pre-clinical model, and its expression can be rescued by non-pharmacological approaches.


NMDAR BDNF-TrkB Medial prefrontal cortex Hippocampus 



JV Lafuente has been a recipient of the IKERMUGIKORTASUNA program (MV 2018-1-33, Basque Government), and he thanks Dr. William Jr. Slikker and Dr. Sherry Ferguson (NCTR, Jefferson AK) for their valuable contribution to the development of this manuscript.

Funding Information

This work has been partially supported by the University of the Basque Country UPV/EHU (EHU 14/33, PPG 17/51) and by the Basque Government (GIC IT 901/16).

Compliance with Ethical Standards

All procedures were performed in accordance with the European Recommendations 2007/526/EC and were approved by the Ethical Committee on Animal Welfare of the University of the Basque Country (UPV/EHU).


  1. 1.
    Lewis DA, Levitt P (2002) Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 25:409–432. CrossRefGoogle Scholar
  2. 2.
    McGlashan TH, Hoffman RE (2000) Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch Gen Psychiatry 57:637–648CrossRefGoogle Scholar
  3. 3.
    Sullivan EM, O'Donnell P (2012) Inhibitory interneurons, oxidative stress, and schizophrenia. Schizophr Bull 38:373–376. CrossRefGoogle Scholar
  4. 4.
    Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A (2009) Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci 32:485–495. CrossRefGoogle Scholar
  5. 5.
    Hashimoto T, Bazmi HH, Mirnics K et al (2008) Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 165:479–489. CrossRefGoogle Scholar
  6. 6.
    Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, Berretta S, Heckers S (2011) Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res 131:165–173. CrossRefGoogle Scholar
  7. 7.
    Morris HM, Hashimoto T, Lewis DA (2008) Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder. Cerebral cortex (New York, NY : 1991) 18:1575–1587. Google Scholar
  8. 8.
    de Jonge JC, Vinkers CH, Hulshoff Pol HE, Marsman A (2017) GABAergic mechanisms in schizophrenia: linking postmortem and in vivo studies. Front Psych 8:118–118. CrossRefGoogle Scholar
  9. 9.
    Toker L, Mancarci BO, Tripathy S, Pavlidis P (2018) Transcriptomic evidence for alterations in astrocytes and parvalbumin interneurons in subjects with bipolar disorder and schizophrenia. Biol Psychiatry 84:787–796. CrossRefGoogle Scholar
  10. 10.
    Fung SJ, Webster MJ, Sivagnanasundaram S, Duncan C, Elashoff M, Weickert CS (2010) Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. Am J Psychiatry 167:1479–1488. CrossRefGoogle Scholar
  11. 11.
    Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, Kim J, Takeuchi H et al (2017) Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 43:764–777. CrossRefGoogle Scholar
  12. 12.
    Murueta-Goyena A, Ortuzar N, Gargiulo PA, Lafuente JV, Bengoetxea H (2018) Short-term exposure to enriched environment in adult rats restores MK-801-induced cognitive deficits and GABAergic interneuron immunoreactivity loss. Mol Neurobiol 55:26–41. CrossRefGoogle Scholar
  13. 13.
    Murueta-Goyena A, Morera-Herreras T, Miguelez C, Gutiérrez-Ceballos A, Ugedo L, Lafuente JV, Bengoetxea H (2019) Effects of adult enriched environment on cognition, hippocampal-prefrontal plasticity and NMDAR subunit expression in MK-801-induced schizophrenia model. Eur Neuropsychopharmacol 29:590–600. CrossRefGoogle Scholar
  14. 14.
    Lim AL, Taylor DA, Malone DT (2012) Consequences of early life MK-801 administration: long-term behavioural effects and relevance to schizophrenia research. Behav Brain Res 227:276–286CrossRefGoogle Scholar
  15. 15.
    Nawa H, Bessho Y, Carnahan J, Nakanishi S, Mizuno K (1993) Regulation of neuropeptide expression in cultured cerebral cortical neurons by brain-derived neurotrophic factor. J Neurochem 60:772–775CrossRefGoogle Scholar
  16. 16.
    Carnahan J, Nawa H (1995) Regulation of neuropeptide expression in the brain by neurotrophins. Potential role in vivo. Mol Neurobiol 10:135–149. CrossRefGoogle Scholar
  17. 17.
    Villuendas G, Sanchez-Franco F, Palacios N et al (2001) Involvement of VIP on BDNF-induced somatostatin gene expression in cultured fetal rat cerebral cortical cells. Brain Res Mol Brain Res 94:59–66CrossRefGoogle Scholar
  18. 18.
    Nawa H, Pelleymounter MA, Carnahan J (1994) Intraventricular administration of BDNF increases neuropeptide expression in newborn rat brain. J Neurosci 14:3751–3765CrossRefGoogle Scholar
  19. 19.
    Yamada K, Nabeshima T (2003) Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 91:267–270CrossRefGoogle Scholar
  20. 20.
    Bekinschtein P, Cammarota M, Medina JH (2014) BDNF and memory processing. Neuropharmacology 76(Pt C):677–683. CrossRefGoogle Scholar
  21. 21.
    Grosse G, Djalali S, Deng DR et al (2005) Area-specific effects of brain-derived neurotrophic factor (BDNF) genetic ablation on various neuronal subtypes of the mouse brain. Brain Res Dev Brain Res 156:111–126. CrossRefGoogle Scholar
  22. 22.
    Urban-Ciecko J, Barth AL (2016) Somatostatin-expressing neurons in cortical networks. Nat Rev Neurosci 17:401–409. CrossRefGoogle Scholar
  23. 23.
    Du X, Serena K, Hwang W et al (2018) Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex. Mol Cell Neurosci 88:177–188. CrossRefGoogle Scholar
  24. 24.
    Glorioso C, Sabatini M, Unger T, Hashimoto T, Monteggia LM, Lewis DA, Mirnics K (2006) Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood. Mol Psychiatry 11:633–648. CrossRefGoogle Scholar
  25. 25.
    Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE (2003) Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 8:592–610. CrossRefGoogle Scholar
  26. 26.
    Weickert CS, Ligons DL, Romanczyk T, Ungaro G, Hyde TM, Herman MM, Weinberger DR, Kleinman JE (2005) Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol Psychiatry 10:637–650CrossRefGoogle Scholar
  27. 27.
    Durany N, Michel T, Zochling R et al (2001) Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 52:79–86CrossRefGoogle Scholar
  28. 28.
    Toyooka K, Asama K, Watanabe Y, Muratake T, Takahashi M, Someya T, Nawa H (2002) Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatry Res 110:249–257CrossRefGoogle Scholar
  29. 29.
    van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191–198. CrossRefGoogle Scholar
  30. 30.
    Bator E, Latusz J, Wedzony K et al (2018) Adolescent environmental enrichment prevents the emergence of schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia. Eur Neuropsychopharmacol 28:97–108CrossRefGoogle Scholar
  31. 31.
    Burrows EL, McOmish CE, Buret LS et al (2015) Environmental enrichment ameliorates behavioral impairments modeling schizophrenia in mice lacking metabotropic glutamate receptor 5. Neuropsychopharmacology 40:1947–1956CrossRefGoogle Scholar
  32. 32.
    Kentner AC, Khoury A, Lima Queiroz E, MacRae M (2016) Environmental enrichment rescues the effects of early life inflammation on markers of synaptic transmission and plasticity. Brain Behav Immun 57:151–160CrossRefGoogle Scholar
  33. 33.
    Nozari M, Shabani M, Hadadi M, Atapour N (2014) Enriched environment prevents cognitive and motor deficits associated with postnatal MK-801 treatment. Psychopharmacology 231:4361–4370. CrossRefGoogle Scholar
  34. 34.
    Nozari M, Shabani M, Farhangi AM, Mazhari S, Atapour N (2015) Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment. Neuroscience 299:28–34CrossRefGoogle Scholar
  35. 35.
    Chang CY, Chen YW, Wang TW, Lai WS (2016) Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions. Sci Rep 6(33095).
  36. 36.
    Funk AJ, McCullumsmith RE, Haroutunian V et al (2012) Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. Neuropsychopharmacology 37:896–905. CrossRefGoogle Scholar
  37. 37.
    Brown JA, Ramikie TS, Schmidt MJ, Báldi R, Garbett K, Everheart MG, Warren LE, Gellért L et al (2015) Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20:1499–1507. CrossRefGoogle Scholar
  38. 38.
    Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324CrossRefGoogle Scholar
  39. 39.
    Hashimoto T, Volk DW, Eggan SM et al (2003) Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 23:6315–6326CrossRefGoogle Scholar
  40. 40.
    Volk DW, Edelson JR, Lewis DA (2016) Altered expression of developmental regulators of parvalbumin and somatostatin neurons in the prefrontal cortex in schizophrenia. Schizophr Res 177:3–9. CrossRefGoogle Scholar
  41. 41.
    Rudy B, Fishell G, Lee SH, Hjerling-Leffler J (2011) Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol 71:45–61. CrossRefGoogle Scholar
  42. 42.
    Dournaud P, Delaere P, Hauw JJ, Epelbaum J (1995) Differential correlation between neurochemical deficits, neuropathology, and cognitive status in Alzheimer’s disease. Neurobiol Aging 16:817–823CrossRefGoogle Scholar
  43. 43.
    Dutar P, Vaillend C, Viollet C, Billard JM, Potier B, Carlo AS, Ungerer A, Epelbaum J (2002) Spatial learning and synaptic hippocampal plasticity in type 2 somatostatin receptor knock-out mice. Neuroscience 112:455–466CrossRefGoogle Scholar
  44. 44.
    Yavorska I, Wehr M (2016) Somatostatin-expressing inhibitory interneurons in cortical circuits. Front Neural Circuits 10(76).
  45. 45.
    Tuncdemir SN, Wamsley B, Stam FJ, Osakada F, Goulding M, Callaway EM, Rudy B, Fishell G (2016) Early somatostatin interneuron connectivity mediates the maturation of deep layer cortical circuits. Neuron 89:521–535. CrossRefGoogle Scholar
  46. 46.
    Abbas AI, Sundiang MJM, Henoch B, Morton MP, Bolkan SS, Park AJ, Harris AZ, Kellendonk C et al (2018) Somatostatin interneurons facilitate hippocampal-prefrontal synchrony and prefrontal spatial encoding. Neuron. 100:926–939.e3. CrossRefGoogle Scholar
  47. 47.
    Arif M, Ahmed MM, Kumabe Y, Hoshino H, Chikuma T, Kato T (2006) Clozapine but not haloperidol suppresses the changes in the levels of neuropeptides in MK-801-treated rat brain regions. Neurochem Int 49:304–311. CrossRefGoogle Scholar
  48. 48.
    Perez-Rando M, Castillo-Gomez E, Guirado R et al (2017) NMDA receptors regulate the structural plasticity of spines and axonal boutons in hippocampal interneurons. Front Cell Neurosci 11(166).
  49. 49.
    van der Staay FJ, Rutten K, Erb C, Blokland A (2011) Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav Brain Res 220:215–229. CrossRefGoogle Scholar
  50. 50.
    von Engelhardt J, Bocklisch C, Tonges L et al (2015) GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice. Front Cell Neurosci 9(95).
  51. 51.
    Kotermanski SE, Johnson JW (2009) Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J Neurosci 29:2774–2779. CrossRefGoogle Scholar
  52. 52.
    Kinnischtzke AK, Sewall AM, Berkepile JM, Fanselow EE (2012) Postnatal maturation of somatostatin-expressing inhibitory cells in the somatosensory cortex of GIN mice. Front Neural Circuits 6.
  53. 53.
    Montminy MR, Bilezikjian LM (1987) Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 328:175–178. CrossRefGoogle Scholar
  54. 54.
    Gleichmann M, Zhang Y, Wood WH 3rd et al (2012) Molecular changes in brain aging and Alzheimer’s disease are mirrored in experimentally silenced cortical neuron networks. Neurobiol Aging 33:205.e201–205.e218. CrossRefGoogle Scholar
  55. 55.
    Kazlauckas V, Pagnussat N, Mioranzza S, Kalinine E, Nunes F, Pettenuzzo L, O.Souza D, Portela LV et al (2011) Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice. Physiol Behav 102:475–480. CrossRefGoogle Scholar
  56. 56.
    Hino M, Kunii Y, Matsumoto J, Wada A, Nagaoka A, Niwa SI, Takahashi H, Kakita A et al (2016) Decreased VEGFR2 expression and increased phosphorylated Akt1 in the prefrontal cortex of individuals with schizophrenia. J Psychiatr Res 82:100–108. CrossRefGoogle Scholar
  57. 57.
    Ishii D, Matsuzawa D, Kanahara N, Matsuda S, Sutoh C, Ohtsuka H, Nakazawa K, Kohno M et al (2010) Effects of aripiprazole on MK-801-induced prepulse inhibition deficits and mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 471:53–57. CrossRefGoogle Scholar
  58. 58.
    Ahn YM, Seo MS, Kim SH, Kim Y, Yoon SC, Juhnn YS, Kim YS (2005) Increased phosphorylation of Ser473-Akt, Ser9-GSK-3beta and Ser133-CREB in the rat frontal cortex after MK-801 intraperitoneal injection. Int J Neuropsychopharmacol 8:607–613CrossRefGoogle Scholar
  59. 59.
    Ahn YM, Seo MS, Kim SH, Kim Y, Juhnn YS, Kim YS (2006) The effects of MK-801 on the phosphorylation of Ser338-c-Raf-MEK-ERK pathway in the rat frontal cortex. Int J Neuropsychopharmacol 9:451–456CrossRefGoogle Scholar
  60. 60.
    Seo MS, Kim SH, Ahn YM, Kim Y, Jeon WJ, Yoon SC, Roh MS, Juhnn YS et al (2007) The effects of repeated administrations of MK-801 on ERK and GSK-3beta signalling pathways in the rat frontal cortex. Int J Neuropsychopharmacol 10:359–368CrossRefGoogle Scholar
  61. 61.
    Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623CrossRefGoogle Scholar
  62. 62.
    Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F et al (2003) Control of synaptic strength, a novel function of Akt. Neuron 38:915–928CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Clinical and Experimental Neuroscience, Department of NeuroscienceUniversity of the Basque Country, UPV/EHULeioaSpain
  2. 2.Neurodegenerative Diseases groupBioCruces Bizkaia Health Research InstituteBarakaldoSpain
  3. 3.Nanoneurosurgery GroupBioCruces Bizkaia Health Research InstituteBarakaldoSpain

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