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  • Original Research Article
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Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

Abstract

Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkBTK+ mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkBTK+ mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkBTK+ mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkBTK+ was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia.

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References

  1. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE . Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003; 8: 592–610.

    Article  CAS  Google Scholar 

  2. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN et al. Relationship of brain-derived neurotrophic factor and its receptor trkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neuro 2005; 25: 372–383.

    Article  CAS  Google Scholar 

  3. Knusel B, Gao H, Okazaki T, Yoshida T, Mori N, Hefti F et al. Ligand-induced down-regulation of Trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Neuroscience 1997; 78: 851–862.

    Article  CAS  Google Scholar 

  4. Morinobu S, Fujimaki K, Okuyama N, Takahashi M, Duman RS . Stimulation of adenyl cyclase and induction of brain-derived neurotrophic factor and TrkB mRNA by NKH477, a novel and potent forskolin derivative. J Neurochem 1999; 72: 2198–2205.

    Article  CAS  Google Scholar 

  5. Nibuya M, Morinobu S, Duman RS . Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15: 7539–7547.

    Article  CAS  Google Scholar 

  6. Nibuya M, Takahashi M, Russell DS, Duman RS . Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 1999; 267: 81–84.

    Article  CAS  Google Scholar 

  7. Chao MV . Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci 2003; 4: 299–309.

    Article  CAS  Google Scholar 

  8. Biffo S, Offenhauser N, Carter BD, Barde YA . Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development 1995; 121: 2461–2470.

    PubMed  CAS  Google Scholar 

  9. Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF . Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 1996; 16: 3123–3129.

    Article  CAS  Google Scholar 

  10. Middlemas DS, Lindberg RA, Hunter T . trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 1991; 11: 143–153.

    Article  CAS  Google Scholar 

  11. Romanczyk TB, Weickert CS, Webster MJ, Herman MM, Akil M, Kleinman JE . Alterations in trkB mRNA in the human prefrontal cortex throughout the lifespan. Eur J Neurosci 2002; 15: 269–280.

    Article  CAS  Google Scholar 

  12. Cheng B, Goodman Y, Begley JG, Mattson MP . Neurotrophin-4/5 protects hippocampal and cortical neurons against energy deprivation- and excitatory amino acid-induced injury. Brain Res 1994; 650: 331–335.

    Article  CAS  Google Scholar 

  13. Linden AM, Vaisanen J, Lakso M, Nawa H, Wong G, Castren E . Expression of neurotrophins BDNF and NT-3, and their receptors in rat brain after administration of antipsychotic and psychotrophic agents. J Mol Neurosci 2000; 14: 27–37.

    Article  CAS  Google Scholar 

  14. Ghosh A, Carnahan J, Greenberg ME . Requirement for BDNF in activity-dependent survival of cortical neurons. Science 1994; 263: 1618–1623.

    Article  CAS  Google Scholar 

  15. Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay RM . Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci 1994; 14: 335–347.

    Article  CAS  Google Scholar 

  16. Larkfors L, Lindsay RM, Alderson RF . Characterization of the responses of Purkinje cells to neurotrophin treatment. J Neurochem 1996; 66: 1362–1373.

    Article  CAS  Google Scholar 

  17. Spenger C, Hyman C, Studer L, Egli M, Evtouchenko L, Jackson C et al. Effects of BDNF on dopaminergic, serotonergic, and GABAergic neurons in cultures of human fetal ventral mesencephalon. Exp Neurol 1995; 133: 50–63.

    Article  CAS  Google Scholar 

  18. Seil FJ . BDNF and NT-4, but not NT-3, promote development of inhibitory synapses in the absence of neuronal activity. Brain Res 1999; 818: 561–564.

    Article  CAS  Google Scholar 

  19. Blum P, Mann J . The GABAergic system in schizophrenia. Int J Neuropsychopharmacol 2002; 5: 159–179.

    Article  CAS  Google Scholar 

  20. Goff DC, Coyle JT . The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001; 158: 1367–1377.

    Article  CAS  Google Scholar 

  21. Lamballe F, Klein R, Barbacid M . trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 1991; 66: 967–979.

    Article  CAS  Google Scholar 

  22. Tessarollo L, Tsoulfas P, Martin-Zanca D, Gilbert DJ, Jenkins NA, Copeland NG et al. trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. Development 1993; 118: 463–475.

    PubMed  CAS  Google Scholar 

  23. Schoups AA, Elliott RC, Friedman WJ, Black IB . NGF and BDNF are differentially modulated by visual experience in the developing geniculocortical pathway. Brain Res Dev Brain Res 1995; 86: 326–334.

    Article  CAS  Google Scholar 

  24. Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME et al. NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 1990; 5: 501–509.

    Article  CAS  Google Scholar 

  25. Morfini G, DiTella MC, Feiguin F, Carri N, Caceres A . Neurotrophin-3 enhances neurite outgrowth in cultured hippocampal large neurons. J Neurosci Res 1994; 39: 219–232.

    Article  CAS  Google Scholar 

  26. McAllister AK, Lo DC, Katz LC . Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 1995; 15: 791–803.

    Article  CAS  Google Scholar 

  27. McAllister AK, Katz LC, Lo DC . Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth. Neuron 1997; 18: 767–778.

    Article  CAS  Google Scholar 

  28. Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P et al. Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 2001; 52: 79–86.

    Article  CAS  Google Scholar 

  29. Dawson E, Powell JF, Sham PC, Nothen M, Crocq MA, Propping P et al. An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia. Acta Psychiatr Scand 1995; 92: 425–428.

    Article  CAS  Google Scholar 

  30. Hattori M, Nanko S . Association of neurotrophin-3 gene variant with severe forms of schizophrenia. Biochem Biophys Res Commun 1995; 209: 513–518.

    Article  CAS  Google Scholar 

  31. Nanko S, Hattori M, Kuwata S, Sasaki T, Fukuda R, Dai XY et al. Neurotrophin-3 gene polymorphism associated with schizophrenia. Acta Psychiatr Scand 1994; 89: 390–392.

    Article  CAS  Google Scholar 

  32. Jonsson E, Brene S, Zhang XR, Nimgaonkar VL, Tylec A, Schalling M et al. Schizophrenia and neurotrophin-3 alleles. Acta Psychiatr Scand 1997; 95: 414–419.

    Article  CAS  Google Scholar 

  33. Virgos C, Martorell L, Valero J, Figuera L, Civeira F, Joven J et al. Association study of schizophrenia with polymorphisms at six candidate genes. Schizophr Res 2001; 49: 65–71.

    Article  CAS  Google Scholar 

  34. Schramm M, Falkai P, Feldmann N, Knable MB, Bayer TA . Reduced tyrosine kinase receptor C mRNA levels in the frontal cortex of patients with schizophrenia. Neurosci Lett 1998; 257: 65–68.

    Article  CAS  Google Scholar 

  35. Weickert CS, Webster MJ, Hyde TM, Herman MM, Bachus SE, Bali G et al. Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia. Cereb Cortex 2001; 11: 136–147.

    Article  CAS  Google Scholar 

  36. Kleinman JE, Hyde TM, Herman MM . Methodological issues in the neuropathology of mental illness. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press, Ltd.: New York, 1995; 859–864.

    Google Scholar 

  37. Allen SJ, Dawbarn D, Eckford SD, Wilcock GK, Ashcroft M, Colebrook SM et al. Cloning of a non-catalytic form of human trkB and distribution of messenger RNA for trkB in human brain. Neuroscience 1994; 60: 825–834.

    Article  CAS  Google Scholar 

  38. Klein R, Conway D, Parada LF, Barbacid M . The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 1990; 61: 647–656.

    Article  CAS  Google Scholar 

  39. Shelton DL, Sutherland J, Gripp J, Camerato T, Armanini MP, Phillips HS et al. Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesions. J Neurosci 1995; 15: 477–491.

    Article  CAS  Google Scholar 

  40. Whitfield Jr HJ, Brady LS, Smith MA, Mamalaki E, Fox RJ, Herkenham M . Optimization of cRNA probe in situ hybridization methodology for localization of glucocorticoid receptor mRNA in rat brain: a detailed protocol. Cell Mol Neurobiol 1990; 10: 145–157.

    Article  CAS  Google Scholar 

  41. Rajkowska G, Goldman-Rakic PS . Cytoarchitectonic definition of prefrontal areas in the normal human cortex: II. Variability in locations of areas 9 and 46 and relationship to the Talairach Coordinate System. Cereb Cortex 1995; 5: 323–337.

    Article  CAS  Google Scholar 

  42. Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004; 61: 544–555.

    Article  CAS  Google Scholar 

  43. Pierri JN, Volk CL, Auh S, Sampson A, Lewis DA . Decreased somal size of deep layer 3 large neurons in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry 2001; 58: 466–473.

    Article  CAS  Google Scholar 

  44. Rajkowska G, Selemon LD, Goldman-Rakic PS . Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 1998; 55: 215–224.

    Article  CAS  Google Scholar 

  45. Glantz LA, Lewis DA . Dendritic spine density in schizophrenia and depression. Arch Gen Psychiatry 2001; 58: 203.

    Article  CAS  Google Scholar 

  46. Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM et al. Reduced dendritic spine density on cerebral cortical large neurons in schizophrenia. J Neurol Neurosurg Psychiatry 1998; 65: 446–453.

    Article  CAS  Google Scholar 

  47. Selemon LD, Rajkowska G, Goldman-Rakic PS . Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 1995; 52: 805–818.

    Article  CAS  Google Scholar 

  48. Selemon LD, Rajkowska G, Goldman-Rakic PS . Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method. J Comp Neurol 1998; 392: 402–412.

    Article  CAS  Google Scholar 

  49. Halim N, Weickert C, McClintock B, Hyde T, Weinberger D, Kleinman J et al. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol Psychiatry 2003; 8: 797–810.

    Article  CAS  Google Scholar 

  50. 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 

  51. Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.

    Article  CAS  Google Scholar 

  52. Jones KR, Farinas I, Backus C, Reichardt LF . Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 1994; 76: 989–999.

    Article  CAS  Google Scholar 

  53. Schwartz P, Borghesani P, Levy R, Pomeroy S, Segal R . Abnormal cerebellar development and foliation in BDNF−/− mice reveals a role for neurotrophins in CNS patterning. Neuron 1997; 19: 269–281.

    Article  CAS  Google Scholar 

  54. Minichiello L, Klein R . TrkB and trkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Genes Dev 1996; 10: 2849–2858.

    Article  CAS  Google Scholar 

  55. Alcantara S, Frisen J, Del Rio JA, Soriano E, Barbacid M, Silos-Santiago I . TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J Neurosci 1997; 17: 3623–3633.

    Article  CAS  Google Scholar 

  56. Gorski J, Zeiler S, Tamowski S, Jones K . Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci 2003; 23: 6856–6865.

    Article  CAS  Google Scholar 

  57. Xu B, Zang K, Ruff NL, Zhang YZ, McConnell SK, Stryker MP et al. Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of receptor TrkB. Neuron 2000; 26: 233–245.

    Article  CAS  Google Scholar 

  58. Schramm M, Falkai P, Tepest R, Schneider-Axmann T, Przkora R, Waha A et al. Stability of RNA transcripts in post-mortem psychiatric brains. J Neural Transm 1999; 106: 329–335.

    Article  CAS  Google Scholar 

  59. Thomson AM, Bannister AP . Postsynaptic large target selection by descending layer III large axons: dual intracellular recordings and biocytin filling in slices of rat neocortex. Neuroscience 1998; 84: 669–683.

    Article  CAS  Google Scholar 

  60. Rico B, Xu B, Reichardt LF . TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 2002; 5: 225–233.

    Article  CAS  Google Scholar 

  61. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase 67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57: 1061–1069.

    Article  CAS  Google Scholar 

  62. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney Jr WE 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 

  63. Akbarian S, Huntsman MM, Kim JJ, Tafazzoli A, Potkin SG, Bunney Jr WE et al. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls. Cereb Cortex 1995; 5: 550–560.

    Article  CAS  Google Scholar 

  64. Beasley C, Zhang Z, Patten I, Reynolds G . Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol Psychiatry 2002; 52: 708.

    Article  CAS  Google Scholar 

  65. Beasley CL, Reynolds GP . Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophr Res 1997; 24: 349–355.

    Article  CAS  Google Scholar 

  66. Benes FM, Vincent SL, Marie A, Khan Y . Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 1996; 75: 1021–1031.

    Article  CAS  Google Scholar 

  67. Lewis DA . GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res Brain Res Rev 2000; 31: 270–276.

    Article  CAS  Google Scholar 

  68. Woo TU, Whitehead RE, Melchitzky DS, Lewis DA . A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci USA 1998; 95: 5341–5346.

    Article  CAS  Google Scholar 

  69. 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 large neurons in schizophrenia. Cereb Cortex 2002; 12: 1063–1070.

    Article  Google Scholar 

  70. Gorba T, Wahle P . Expression of TrkB and TrkC but not BDNF mRNA in neurochemically identified interneurons in rat visual cortex in vivo and in organotypic cultures. Eur J Neurosci 1999; 11: 1179–1190.

    Article  CAS  Google Scholar 

  71. Kokaia Z, Metsis M, Kokaia M, Elmer E, Lindvall O . Co-expression of TrkB and TrkC receptors in CNS neurons suggests regulation by multiple neurotrophins. NeuroReport 1995; 6: 769–772.

    Article  CAS  Google Scholar 

  72. Vicario-Abejon C, Collin C, McKay RD, Segal M . Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. J Neurosci 1998; 18: 7256–7271.

    Article  CAS  Google Scholar 

  73. Martinez A, Alcantara S, Borrell V, Del Rio JA, Blasi J, Otal R et al. TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. J Neurosci 1998; 18: 7336–7350.

    Article  CAS  Google Scholar 

  74. Nimgaonkar VL, Zhang XR, Brar JS, DeLeo M, Ganguli R . Lack of association of schizophrenia with the neurotrophin-3 gene locus. Acta Psychiatr Scand 1995; 92: 464–466.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the following people who assisted in this research project: Juraj Cervenak MD, Sarah Colvin, MD, Robert Fatula, Subroto Ghose, MD, PhD, and Yeva Snitkovsky.

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Weickert, C., Ligons, D., Romanczyk, T. et al. Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol Psychiatry 10, 637–650 (2005). https://doi.org/10.1038/sj.mp.4001678

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