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Effects of haloperidol and clozapine on synapse-related gene expression in specific brain regions of male rats

  • Martina von Wilmsdorff
  • Fabian Manthey
  • Marie-Luise Bouvier
  • Oliver Staehlin
  • Peter Falkai
  • Eva Meisenzahl-Lechner
  • Andrea Schmitt
  • Peter J. Gebicke-Haerter
Original Paper
  • 84 Downloads

Abstract

We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs’ effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded.

Keywords

Presynaptic proteins Cytoskeletal proteins BDNF Gene expression Schizophrenia 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

406_2018_872_MOESM1_ESM.docx (361 kb)
Supplementary material 1 (DOCX 361 KB)

References

  1. 1.
    Kircher T, Thienel R (2006) Functional brain imaging of symptoms and cognition in schizophrenia. The boundaries of consciousness. Elsevier, Amsterdam, p 302Google Scholar
  2. 2.
    Harrison PJ, Eastwood SL (2001) Neuropathological studies of synaptic connectivity in the hippocampal formation in Schizophrenia. Hippocampus 11(5):508–519CrossRefPubMedGoogle Scholar
  3. 3.
    Balu DT, Coyle JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35(3):848–870CrossRefPubMedGoogle Scholar
  4. 4.
    Stephan KE, Baldeweg T, Friston KJ (2006) Synaptic plasticity and disconnection in schizophrenia. Biol Psychiatry 59:929–939CrossRefPubMedGoogle Scholar
  5. 5.
    Gray LJ, Dean B, Kronsbein HC, Robinson PJ, Scarr E (2010) Region and diagnosis-specific changes in synaptic proteins in schizophrenia and bipolar I disorder. Psychiatry Res 178(2):374–380CrossRefPubMedGoogle Scholar
  6. 6.
    Bowden NA, Scott RJ, Tooney PA (2008) Altered gene expression in the superior temporal gyrus in schizophrenia. BMC Genom 9:199–211CrossRefGoogle Scholar
  7. 7.
    Schmitt A, Leonardi-Essmann F, Durrenberger PP, Wichert SP, Spanagel R, Arzberger T, Kretzschmar H, Zink M, Herrera-Marscitz M, Reynolds R, Rossner MJ, Falkai P, Gebicke-Haerter PJ (2012) Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients. Eur Arch Psychiatry Clin Neurosci 262:565–577CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Barakauskas VE, Beasley CL, Barr AM, Ypsilanti AR, Li HY, Thornton AE, Wong H, Rosokilja G, Mann JJ, Mancevski B, Jakovski Z, Davceva N, Ilievski B, Dwork AJ, Falkai P, Honer WG (2010).A novel mechanism and treatment target for presynaptic abnormalities in specific striatal regions in schizophrenia. Neuropsychopharmacology 35(5):1226–1238CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Barakauskas VE, Moradian A, Barr AM, Beasley CL, Rosoklija G, Mann JJ, Ilievski B, Stankov A, Dwork AJ, Falkai P, Morin GB, Honer WG (2016) Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia. Schizophr Res 177(1–3):44–51CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pantazopoulos H, Woo TW, Lim MP, Lange N, Berretta S (2010) Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 67(2):155–166CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fulton E (2009) Dynactin is a progressivity factor for dynein in vivo. Thesis, FloridaGoogle Scholar
  12. 12.
    Yao H, Kim HW, Mo J, Lee D, Han S, Koh MJ, Sun W, Choi S, Rhyu IJ, Kim H, Lee HW (2012) Developmental expression and subcellular distribution of synaptotagmin 11 in rat hippocampus. Neuroscience 225:35–43CrossRefGoogle Scholar
  13. 13.
    Castillo MA, Ghose S, Tamminga CA, Ulery-Reynolds PG (2010) Deficits in syntaxin 1 phosphorylation in schizophrenia prefrontal cortex. Biol Psychiatry 67(3):208–216CrossRefPubMedGoogle Scholar
  14. 14.
    McMahon HT, Bolshakov VY, Janz R, Hammer RE, Siegelbaum SA, Südhof TC (1996) Synaptophysin, a major synaptic vesicle protein is not essential for neurotransmitter release. Proc Natl Acad Sci USA 93(10):4760–4764CrossRefPubMedGoogle Scholar
  15. 15.
    Schmitt U, Tanimoto N, Seeliger M, Schaeffel F, Leube RE (2009) Detection of behavioral alterations and learning deficits in mice lacking synaptophysin. Neuroscience 162(2):234–243CrossRefPubMedGoogle Scholar
  16. 16.
    Young CE, Arima K, Xie J, Hu L, Beach TG, Falkai P, Honer WG (1998) SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex 8(3):261–268CrossRefPubMedGoogle Scholar
  17. 17.
    Antonucci F, Corradini I, Morini R, Fossati G, Menna E, Pozzi D, Pacioni S, Verderio C, Bacci A, Matteoli M (2013) Reduced SNAP-25 alters short-term plasticity at developing glutamatergic synapses. EMBO Rep 14(7):645–651CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Fernandes BS, Steiner J, Berk M, Molendijk ML, Gonzalez-Pinto A, Turck CW, Nardin P, Goncalves CA (2015) Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol Psychiatry 20(9):1108–1119CrossRefPubMedGoogle Scholar
  19. 19.
    Qin XY, Wu HT, Cao C, Loh YP, Cheng Y (2017) A meta-analysis of peripheral blood nerve growth factor levels in patients with schizophrenia. Mol Psychiatry 22(9):1306–1312CrossRefPubMedGoogle Scholar
  20. 20.
    Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ (2011) Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 16(9):960–972CrossRefPubMedGoogle Scholar
  21. 21.
    Naoe Y, Shinkai T, Hori H, Fukunaka Y, Utsunimiva K, Sakata S, Matsumoto C, Shimizu K, Hwang R, Ohmori O, Nakamura J (2007) No association between the brain-derived neurotrophic factor (BDNF) Vall66Met polymorphism and schizophrenia in Asian populations: evidence from a case-control study and meta-analysis. Neurosci Lett 415(2):108–112CrossRefPubMedGoogle Scholar
  22. 22.
    De Bartolomeis A, Marmo F, Buonaguro EF, Rossi R, Tomasetti C, Iasevoli F (2013) Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. Eur Neuropsychopharmacol 23(11):1516–1529CrossRefPubMedGoogle Scholar
  23. 23.
    Rizig MA, McQuillin A, Ng A, Robinson M, Harrison A, Zvelebil M, Hunt SP, Gurling HM (2012) A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia. J Psychopharmacol 26(9):1218–1230CrossRefPubMedGoogle Scholar
  24. 24.
    Scarr E, Dean B (2012) Altered neuronal markers following treatment with mood stabilizer and antipsychotic drugs indicate an increased likelihood of neurotransmitter release. Clin Psychopharmacol Neurosci 10(1):25–33CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Barr AM, Young CE, Phillips AG, Honer WG (2006) Selective effects of typical antipsychotic drugs on SNAP-25 and synaptophysin in the hippocampal trisynaptic pathway. Int J Neuropsychopharmacol 9(4):457–463CrossRefPubMedGoogle Scholar
  26. 26.
    von Wilmsdorff M, Bouvier ML, Henning U, Schmitt A, Schneider-Axmann T, Gaebel W (2013) The sex-dependent impact of chronic clozapine and haloperidol treatment on characteristics of the metabolic syndrome in a rat model. Pharmacopsychiatry 46(1):1–9Google Scholar
  27. 27.
    Minet-Ringuet J, Even PC, Goubern M, Tomé P, de Beaurepaire R (2006) Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermic alteration. Appetite 46:254–262CrossRefPubMedGoogle Scholar
  28. 28.
    Minet-Ringuet J, Even PC, Lacroix M, Tomé P, de Beaurepaire R (2006) A model for antipsychotic-induced obesity in the male rat. Psychopharmacology 187:447–454CrossRefPubMedGoogle Scholar
  29. 29.
    Kapur S, Wadenberg ML, Remington G (2000) Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench. Can J Psychiatry 45:241–246CrossRefPubMedGoogle Scholar
  30. 30.
    Paxinos G, Watson C (1999) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San DiegoGoogle Scholar
  31. 31.
    Schmitt A, Hasan A, Gruber O, Falkai P (2011) Schizophrenia as a disorder of disconnectivity. Eur Arch Psychiatry Clin Neurosci 261(Suppl 2):S150–S154CrossRefPubMedGoogle Scholar
  32. 32.
    Hu K, Carroll J, Fedorovich S, Rickman C, Sukhodub A, Davletov B (2002) Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion. Nature 415:646–650CrossRefPubMedGoogle Scholar
  33. 33.
    Kontkanen O, Törönen P, Lakso M, Wong G, Castrén E (2002) Antipsychotic drug treatment induces differential gene expression in the rat cortex. J Neurochem 83:1043–1053CrossRefPubMedGoogle Scholar
  34. 34.
    Carlsson A, Waters N, Carlsson ML (1999) Neurotransmitter interactions in schizophrenia-therapeutic implications. Biol Psychiatry 46(1):1388–1395CrossRefPubMedGoogle Scholar
  35. 35.
    MacDonald ML, Eaton ME, Dudman JT, Konradi C (2005) Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat. Biol Psychiatry 57:1041–1051CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Khoshnoodi J, Pedchenko V, Hudson BG (2008) Mammalian collagen IV. Microsc Res Tech 71(5):357–370CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Halfter W, Yip J (2014) An organizing function of basement membranes in the developing nervous system. Mech Dev 133:1–10CrossRefPubMedGoogle Scholar
  38. 38.
    Dityatev A, Schachner M (2003) Extracellular matrix molecules and synaptic plasticity. Nat Rev 4:456–468CrossRefGoogle Scholar
  39. 39.
    Mallik R, Gross SP (2004) Molecular motors: strategies to get along. Curr Biol 14(22):R971-R982CrossRefGoogle Scholar
  40. 40.
    Mead CL, Kuzyk MA, Moradian A, Wilson GM, Holt RA, Morin GB (2010) Cytosolic protein interactions of the schizophrenia susceptibility gene dysbindin. J Neurochem 113:1491–1503PubMedGoogle Scholar
  41. 41.
    Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P et al (2001) Brain-derived neurotrophic factor and neurotrophin3 in schizophrenic psychoses. Schizophr Res 52:79–86CrossRefPubMedGoogle Scholar
  42. 42.
    Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM (2002) Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 954:11–20CrossRefPubMedGoogle Scholar
  43. 43.
    Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotguns vs magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3(4):353–359CrossRefPubMedGoogle Scholar
  44. 44.
    Sommer JU, Schmitt A, Heck M, Schaeffer EL, Fendt M, Zink M, Nieselt K, Symons S, Petroianu G, Lex A, Herrera-Marschitz M, Spanagel R, Falkai P, Gebicke-Haerter PJ (2010) Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia. Eur Arch Psychiatry Clin Neurosci 260(Suppl 2):S81–9CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Martina von Wilmsdorff
    • 1
  • Fabian Manthey
    • 2
  • Marie-Luise Bouvier
    • 3
  • Oliver Staehlin
    • 4
  • Peter Falkai
    • 5
  • Eva Meisenzahl-Lechner
    • 1
  • Andrea Schmitt
    • 5
    • 6
  • Peter J. Gebicke-Haerter
    • 7
    • 8
  1. 1.Department of Psychiatry and Psychotherapy, Medical FacultyHeinrich-Heine-UniversityDüsseldorfGermany
  2. 2.Department of Psychiatry and PsychotherapyAlexianer Krefeld GmbHKrefeldGermany
  3. 3.Laboratory of Brain Morphology, Department of Psychiatry and Psychotherapy, LVR KlinikumHeinrich-Heine-UniversityDüsseldorfGermany
  4. 4.Thermo Fisher Sci.DarmstadtGermany
  5. 5.Department of Psychiatry and PsychotherapyLudwig Maximilians-University (LMU) MunichMunichGermany
  6. 6.Laboratory of Neuroscience (LIM27), Institute of PsychiatryUniversity of Sao PauloSão PauloBrazil
  7. 7.Central Institute of Mental HealthMedical Faculty Mannheim/Heidelberg UniversityMannheimGermany
  8. 8.Facultad de MedicinaUniversidad de ChileSantiagoChile

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