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Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients

Molecular Psychiatry volume 5, pages 293–300 (2000)Cite this article

Abstract

Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness.

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References

  1. Weinberger DR . Implication of normal brain development for the pathogenesis of schizophrenia Arch Gen Psychiatry 1987; 44: 660–669

    Article  CAS  Google Scholar 

  2. Waddington JL . Schizophrenia: developmental neuroscience and pathobiology Lancet 1993; 341: 531–536

    Article  CAS  Google Scholar 

  3. Stoop R, Poo MM . Synaptic modulation by neurotrophic factors Prog Brain Res 1996; 109: 359–364

    Article  CAS  Google Scholar 

  4. Lewin GR, Barde YA . Physiology of the neurotrophins Ann Rev Neurosci 1996; 19: 289–317

    Article  CAS  Google Scholar 

  5. Schuman EM . Neurotrophin regulation of synaptic transmission Curr Opin Neurobiol 1999; 9: 105–109

    Article  CAS  Google Scholar 

  6. Jankowsky JL, Patterson PH . Cytokine and growth factor involvement in long term potentiation Molec Cell Neurosci 1999; 14: 273–286

    CAS  PubMed  Google Scholar 

  7. Cabelli RJ, Hohn A, Shatz CJ . Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF Science 1995; 267: 1662–1666

    Article  CAS  Google Scholar 

  8. Prakash N, Cohen CS, Frostig RD . Rapid and opposite effects of BDNF and NGF on the functional organization of the adult cortex in vivo Nature 1996; 381: 702–706

    Article  CAS  Google Scholar 

  9. Ringstedt T, Linnarsson S, Wagner J, Lendahl U, Kokaia Z, Arenas E et al. BDNF regulates reelin expression and Cajal–Retzius cell development in the cerebral cortex Neuron 1998; 21: 305–315

    Article  CAS  Google Scholar 

  10. Nawa H, Pelleymounter MA, Carnahan J . Intraventricular administration of BDNF increases neuropeptide expression in newborn rat brain J Neurosci 1994; 14: 3751–3765

    Article  CAS  Google Scholar 

  11. Mizuno K, Carnahan J, Nawa H . Brain-derived neurotrophic factor promotes differentiation of striatal GABAergic neurons Dev Biol 1994; 165: 243–256

    Article  CAS  Google Scholar 

  12. Ahmed S, Reynolds BA, Weiss S . BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors J Neurosci 1995; 15: 5765–5778

    Article  CAS  Google Scholar 

  13. Takei N, Sasaoka K, Inoue K, Takahashi M, Endo Y, Hatanaka H . Brain-derived neurotrophic factor increases the stimulation-evoked release of glutamate and the levels of exocytosis-associated proteins in cultured cortical neurons from embryonic rats J Neurochem 1997; 68: 370–375

    Article  CAS  Google Scholar 

  14. Marty S, Berninger B, Carroll P, Thoenen H . GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor Neuron 1996; 16: 565–570

    Article  CAS  Google Scholar 

  15. Narisawa-Saito M, Carnahan J, Araki K, Yamaguchi T, Nawa H . Brain-derived neurotrophic factor regulates the expression of AMPA receptor proteins in neocortical neurons Neuroscience 1999; 88: 1009–1014

    Article  CAS  Google Scholar 

  16. Korsching S, Thoenen H . Two-site enzyme immunoassay for nerve growth factor Meth Enzymol 1987; 147: 167–185

    Article  CAS  Google Scholar 

  17. Nawa H, Carnahan J, Gall C . BDNF protein measured by a novel enzyme immunoassay in normal brain and after seizure: partial disagreement with mRNA levels Eur J Neurosci 1995; 7: 1527–1535

    Article  CAS  Google Scholar 

  18. Frank L, Ventimiglia R, Anderson K, Lindsay RM, Rudge JS . BDNF down-regulates neurotrophin responsiveness, TrkB protein and TrkB mRNA levels in cultured rat hippocampal neurons Eur J Neurosci 1996; 8: 1220–1230

    Article  CAS  Google Scholar 

  19. Nieuwenhunhuys, R, Voogd J, van Huijzen CHR . The Human Central Nervous System—A Synopsis and Atlas Springer-Verlag, Berlin 1988

    Book  Google Scholar 

  20. Pappas IS, Parnavelas JG . Neurotrophins and basic fibroblast growth factor induce the differentiation of calbindin-containing neurons in the cerebral cortex Exp Neurol 1997; 144: 302–314

    Article  CAS  Google Scholar 

  21. Sokolov BP . Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of ‘neuroleptic-free’ schizophrenics: evidence on reversible up-regulation by typical neuroleptics J Neurochem 1998; 71: 2454–2464

    Article  CAS  Google Scholar 

  22. McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME et al. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status Am J Psychiatry 1995; 152: 1291–1297

    Article  CAS  Google Scholar 

  23. Narisawa-Saito M, Wakabayashi K, Tsuji S, Takahashi H, Nawa H . Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease Neuroreport 1996; 7: 2925–2928

    Article  CAS  Google Scholar 

  24. Zafra F, Hengerer B, Leibrock J, Thoenen H, Lindholm D . Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors EMBO J 1990; 9: 3545–3550

    Article  CAS  Google Scholar 

  25. Bessho Y, Nakanishi S, Nawa H . Glutamate receptor agonists enhance the expression of BDNF mRNA in cultured cerebellar granule cells Mol Brain Res 1993; 18: 201–208

    Article  CAS  Google Scholar 

  26. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN et al. Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome Arch Gen Psychiatry 1992; 49: 522–530

    Article  CAS  Google Scholar 

  27. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RSJ . Pattern of cerebral blood flow in schizophrenia Br J Psychiatry 1982; 160: 179–186

    Article  Google Scholar 

  28. Olney JW, Farber NB . Glutamate receptor dysfunction and schizophrenia Arch Gen Psychiatry 1995; 52: 998–1007

    Article  CAS  Google Scholar 

  29. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA . Ketamine activates psychosis and alters limbic blood flow in schizophrenia Neuroreport 1995; 6: 869–872

    Article  CAS  Google Scholar 

  30. Castren E, da Penha Berzaghi M, Lindholm D, Thoenen H . Differential effects of MK-801 on brain-derived neurotrophic factor mRNA levels in different regions of the rat brain Exp Neurol 1993; 122: 244–252

    Article  CAS  Google Scholar 

  31. Harrison PJ, McLaughlin D, Kerwin RW . Decreased hippocampal expression of a glutamate receptor gene in schizophrenia Lancet 1991; 337: 450–452

    Article  CAS  Google Scholar 

  32. Eastwood SL, McDonald B, Burnet PW, Beckwith JP, Kerwin RW, Harrison PJ . Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia Mol Brain Res 1995; 29: 211–223

    Article  CAS  Google Scholar 

  33. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics Arch Gen Psychiatry 1995; 52: 258–266

    Article  CAS  Google Scholar 

  34. Eastwood SL, Burnet PW, Harrison PJ . Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia Neuroscience 1995; 66: 309–319

    Article  CAS  Google Scholar 

  35. Glantz LA, Lewis DA . Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity Arch Gen Psychiatry 1997; 54: 660–669

    Article  CAS  Google Scholar 

  36. Gabriel SM, Davidson M, Haroutunian V, Powchik P, Bierer LM, Purohit DP et al. Neuropeptide deficits in schizophrenia vs Alzheimer's disease cerebral cortex Biol Psychiatry 1996; 39: 82–91

    Article  CAS  Google Scholar 

  37. Nemeroff CB, Youngblood WW, Manberg PJ, Prange AJ-Jr, Kizer JS . Regional brain concentrations of neuropeptides in Huntington's chorea and schizophrenia Science 1983; 221: 972–975

    Article  CAS  Google Scholar 

  38. Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A et al. Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats Proc Natl Acad Sci USA 1998; 95: 3221–3226

    Article  CAS  Google Scholar 

  39. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia Proc Natl Acad Sci USA 1998; 22: 15718–15723

    Article  Google Scholar 

  40. Arnold SE, Hyman BT, Van HG, Damasio AR . Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia Arch Gen Psychiatry 1991; 48: 625–632

    Article  CAS  Google Scholar 

  41. Conrad AJ, Abebe T, Austin R, Forsythe S, Scheibel AB . Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon Arch Gen Psychiatry 1991; 48: 413–417

    Article  CAS  Google Scholar 

  42. Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE Jr, Jones EG . Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients Arch Gen Psychiatry 1996; 53: 425–436

    Article  CAS  Google Scholar 

  43. D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T . A protein related to extracellular matrix proteins deleted in the mouse mutant reeler Nature 1995; 374: 719–723

    Article  CAS  Google Scholar 

  44. Del Rio JA, Heimrich B, Borrell V, Forster E, Drakew A, Alcantara S et al. A role for Cajal–Retzius cells and reelin in the development of hippocampal connections Nature 1997; 385: 70–74

    Article  CAS  Google Scholar 

  45. Chlan-Fourney J, Li X-M, Juorio AV, Ashe P, Boulton AA . Differential regulation of brain derived neurotrophic factor (BDNF) mRNA in rat brain by chronic haloperidol, risperidone and clozapine treatment Soc Neurosci Abs 1998; 24: 295.4

    Google Scholar 

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Acknowledgements

We thank Sumitomo Pharmaceuticals for supplying the human recombinant BDNF, Dr R Kuwano for anti-calbindin-D antiserum, Dr N Nishino and Mr H Jourdi for advice and Mrs K Hatano for technical assistance. This work was supported by the Japanese Society for the Promotion of Science (RFTF-96L00203) and Grant-in-Aid for Scientific Research (MESSC).

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Author notes

  1. N Kitamura

    Present address: Kobe City Central Hospital, Kobe, Japan

Authors and Affiliations

  1. Molecular Neurobiology, Brain Research Institute, Niigata University, 951–8585, Japan

    M Takahashi, K Toyooka & H Nawa

  2. Department of Psychiatry, Niigata University School of Medicine, 951–8510, Japan

    M Takahashi & T Someya

  3. Department of Psychiatry and Neurology, Kobe University School of Medicine, 650–0017, Japan

    O Shirakawa, N Kitamura, T Hashimoto & K Maeda

  4. Novartis Pharma, Takarazuka, Hyogo Pref, 665–8666, Japan

    S Koizumi

  5. Pathology & Brain Disease Research Center, Brain Research Institute, Niigata University, 951–8585, Japan

    K Wakabayashi & H Takahashi

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Takahashi, M., Shirakawa, O., Toyooka, K. et al. Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 5, 293–300 (2000). https://doi.org/10.1038/sj.mp.4000718

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