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  • Lilly-Molecular Psychiatry Award Honorable Mention
  • Published:

Honorable Mention: Lilly-Molecular Psychiatry Award

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia

Abstract

Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean=23%) and protein (mean=40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder.

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References

  1. Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P et al. Molecular cloning and expression of brain-derived neurotrophic factor. Nature 1989; 341: 149–152.

    Article  CAS  PubMed  Google Scholar 

  2. Lewin GR . Neurotrophins and the specification of neuronal phenotype. Philos Trans R Soc London B Biol Sci 1996; 351: 405–411.

    Article  CAS  PubMed  Google Scholar 

  3. Maisonpierre PC, Le Beau MM, Espinosa III R, Ip NY, Belluscio L, de la Monte SM et al. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 1991; 10: 558–568.

    Article  CAS  PubMed  Google Scholar 

  4. Bothwell M . Functional interactions of neurotrophins and neurotrophin receptors. Annu Rev Neurosci 1995; 18: 223–253.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Lindholm D, Dechant G, Heisenberg CP, Thoenen H . Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity. Eur J Neurosci 1993; 5: 1455–1464.

    Article  CAS  PubMed  Google Scholar 

  7. Cheng B, Mattson MP . NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 1994; 640: 56–67.

    Article  CAS  PubMed  Google Scholar 

  8. McAllister AK, Katz LC, Lo DC . Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 1996; 17: 1057–1064.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Thoenen H . Neurotrophins and neuronal plasticity. Science 1995; 270: 593–598.

    Article  CAS  PubMed  Google Scholar 

  11. Kang H, Schuman EM . Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 1995; 267: 1658–1662.

    Article  CAS  PubMed  Google Scholar 

  12. 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  PubMed  PubMed Central  Google Scholar 

  13. Gwag BJ, Springer JE . Activation of NMDA receptors increases brain-derived neurotrophic factor BDNF mRNA expression in the hippocampal formation. Neuroreport 1993; 5: 125–128.

    Article  CAS  PubMed  Google Scholar 

  14. Friedman WJ, Ernfors P, Persson H . Transient and persistent expression of NT-3/BDNF mRNA in the rat brain during postnatal development. J Neurosci 1991; 11: 1577–1584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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  PubMed  Google Scholar 

  16. Dugich-Djordjevic MM, Tocco G, Willoughby DA, Najm I, Pasinetti G, Thompson RF et al. BDNF mRNA expression in the developing rat brain following kainic acid-induced seizure activity. Neuron 1992; 8: 1127–1138.

    Article  CAS  PubMed  Google Scholar 

  17. Ringstedt T, Lagercrantz H, Persson H . Expression of members of the trk family in the developing postnatal rat brain. Brain Res Dev Brain Res 1993; 72: 119–131.

    Article  CAS  PubMed  Google Scholar 

  18. Knusel B, Rabin SJ, Hefti F, Kaplan DR . Regulated neurotrophin receptor responsiveness during neuronal migration and early differentiation. J Neurosci 1994; 14: 1542–1554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Katoh-Semba R, Takeuchi I K, Semba R, Kato K . Distribution of brain-derived neurotrophic factor in rats and its changes with development in the brain. J Neurochem 1997; 69: 34–42.

    Article  CAS  PubMed  Google Scholar 

  20. Itami C, Mizuno K, Kohno T, Nakamura S . Brain-derived neurotrophic factor requirement for activity-dependent maturation of glutamatergic synapse in developing mouse somatosensory cortex. Brain Res 2000; 857: 141–150.

    Article  CAS  PubMed  Google Scholar 

  21. Weickert CS, Kleinman JE . The neuroanatomy and neurochemistry of schizophrenia. Psychiatr Clin North Am 1998; 21: 57–75.

    Article  CAS  PubMed  Google Scholar 

  22. Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE et al. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 1995; 52: 829–836.

    Article  CAS  PubMed  Google Scholar 

  23. Bertolino A, Callicott JH, Elman I, Mattay VS, Tedeschi G, Frank JA et al. Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 1998; 43: 641–648.

    Article  CAS  PubMed  Google Scholar 

  24. Bertolino A Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CT et al. Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 1996; 153: 1554–1563.

    Article  CAS  PubMed  Google Scholar 

  25. Block W, Bayer TA, Tepest R, Traber F, Rietschel M, Muller D et al. Decreased frontal lobe ratio of N-acetyl aspartate to choline in familial schizophrenia: a proton magnetic resonance spectroscopy study. Neurosci Lett 2000; 289: 147–151.

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Vawter MP, Crook JM, Hyde TM, Kleinman JE, Weinberger DR, Becker KG et al. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia. Schizophr Res 2002; 58: 11–20.

    Article  PubMed  Google Scholar 

  28. 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. Cerebr Cortex 2001; 11: 136–147.

    Article  CAS  Google Scholar 

  29. 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  PubMed  Google Scholar 

  30. Honer WG, Falkai P, Chen C, Arango V, Mann JJ, Dwork AJ et al. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience 1999; 91: 1247–1255.

    Article  CAS  PubMed  Google Scholar 

  31. Karson CN, Mrak RE, Schluterman KO, Sturner WQ, Sheng JG, Griffin WS et al. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for ‘hypofrontality’. Mol Psychiatry 1999; 4: 39–45.

    Article  CAS  PubMed  Google Scholar 

  32. Thompson PM, Sower AC, Perrone-Bizzozero NI . Altered levels of the synaptosomal associated protein SNAP-25 in schizophrenia. Biol Psychiatry 1998; 43: 239–243.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. 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; discussion 819–820.

    Article  CAS  PubMed  Google Scholar 

  38. 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  PubMed  Google Scholar 

  39. Harrison PJ, Eastwood SL . Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 2001; 11: 508–519.

    Article  CAS  PubMed  Google Scholar 

  40. Heckers S, Konradi C . Hippocampal neurons in schizophrenia. J Neural Transm 2002; 109: 891–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Weickert CS, Weinberger DR . A candidate molecule approach to defining developmental pathology in schizophrenia. Schizophr Bull 1998; 24: 303–316.

    Article  CAS  PubMed  Google Scholar 

  42. Causing CG, Gloster A, Aloyz R, Bamji SX, Chang E, Fawcett J et al. Synaptic innervation density is regulated by neuron-derived BDNF. Neuron 1997; 18: 257–267.

    Article  CAS  PubMed  Google Scholar 

  43. Wetmore C, Ernfors P, Persson H, Olson L . Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization. Exp Neurol 1990; 109: 141–152.

    Article  CAS  PubMed  Google Scholar 

  44. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW et al. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 1991; 7: 695–702.

    Article  CAS  PubMed  Google Scholar 

  45. Lipska BK, Khaing ZZ, Weickert CS, Weinberger DR . BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci 2001; 14: 135–144.

    Article  CAS  PubMed  Google Scholar 

  46. Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA . Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 1990; 9: 2459–2464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huntley GW, Benson DL, Jones EG, Isackson PJ . Developmental expression of brain derived neurotrophic factor mRNA by neurons of fetal and adult monkey prefrontal cortex. Brain Res Dev Brain Res 1992; 70: 53–63.

    Article  CAS  PubMed  Google Scholar 

  48. Kleinman JE, Hyde TM, Herman MM . In: Bloom FE and Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press Ltd: New York, 1995, pp 859–864.

    Google Scholar 

  49. Rajkowska G, Goldman-Rakic PS . Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria. Cerebr Cortex 1995; 5: 307–322.

    Article  CAS  Google Scholar 

  50. Torrey EF . In: Surviving Schizophrenia. Harper & Row: New York, 1983, p 188.

  51. Sambrook J, Fritsch EF, Maniatis T . Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Press: Cold Spring Harbor, NY, 1989.

    Google Scholar 

  52. Lazar LM, Blum M . Regional distribution and developmental expression of epidermal growth factor and transforming growth factor-alpha mRNA in mouse brain by a quantitative nuclease protection assay. J Neurosci 1992; 12: 1688–1697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedman WJ, Black IB, Kaplan DR . Distribution of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the postnatal rat brain: an immunocytochemical study. Neuroscience 1998; 84: 101–114.

    Article  CAS  PubMed  Google Scholar 

  54. Whitfield Jr HJ, Brady LS, Smith MA, Mamalaki E, Fox RJ, Kerkenham M et al. 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  PubMed  Google Scholar 

  55. Hayashi M, Yamashita A, Shimizu K . Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNAs during aging. Brain Res 1997; 283–289.

  56. Tokuyama W, Okuno H, Hashimoto T, Xin Li Y, Miyashita Y . BDNF upregulation during declarative memory formation in monkey inferior temporal cortex. Nat Neurosci 2000; 3: 1134–1142.

    Article  CAS  PubMed  Google Scholar 

  57. Hashimoto T, Okuno H, Tokuyama W, Li YX, Miyashita Y . Expression of brain-derived neurotrophic factor, neurotrophin-3 and their receptor messenger RNAs in monkey rhinal cortex. Neuroscience 2000; 95: 1003–1010.

    Article  CAS  PubMed  Google Scholar 

  58. 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  PubMed  Google Scholar 

  59. Linden AM, Vaisanen J, Lakso M, Nawa H, Wong G, Castren E et al. 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  PubMed  Google Scholar 

  60. Angelucci F, Aloe L, Vasquez PJ, Mathe AA . Mapping the differences in the brain concentration of brain-derived neurotrophic factor BDNF and nerve growth factor NGF in an animal model of depression. Neuroreport 2000; 11: 1369–1373.

    Article  CAS  PubMed  Google Scholar 

  61. Dawson NM, Hamid EH, Egan MF, Meredith GE . Changes in the pattern of brain-derived neurotrophic factor immunoreactivity in the rat brain after acute and subchronic haloperidol treatment. Synapse 2001; 39: 70–81.

    Article  CAS  PubMed  Google Scholar 

  62. Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K . Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5: 293–300.

    Article  CAS  PubMed  Google Scholar 

  63. Cabelli RJ, Shelton DL, Segal RA, Shatz CJ . Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns. Neuron 1997; 19: 63–76.

    Article  CAS  PubMed  Google Scholar 

  64. Linnarsson S, Bjorklund A, Ernfors P . Learning deficit in BDNF mutant mice. Eur J Neurosci 1997; 9: 2581–2587.

    Article  CAS  PubMed  Google Scholar 

  65. Mu JS, Li WP, Yao ZB, Zhou XF . Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 1999; 835: 259–265.

    Article  CAS  PubMed  Google Scholar 

  66. Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T . Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 2000; 20: 7116–7121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 1993; 10: 475–489.

    Article  CAS  PubMed  Google Scholar 

  68. Timmusk T, Metsis M . Regulation of BDNF promoters in the rat hippocampus. Neurochem Int 1994; 25: 11–15.

    Article  CAS  PubMed  Google Scholar 

  69. Timmusk T, Belluardo N, Persson H, Metsis M . Developmental regulation of brain-derived neurotrophic factor messenger RNAs transcribed from different promoters in the rat brain. Neuroscience 1994; 60: 287–291.

    Article  CAS  PubMed  Google Scholar 

  70. Nanda S, Mack KJ . Multiple promoters direct stimulus and temporal specific expression of brain-derived neurotrophic factor in the somatosensory cortex. Brain Res Mol Brain Res 1998; 62: 216–219.

    Article  CAS  PubMed  Google Scholar 

  71. Nakayama M, Gahara Y, Kitamura T, Ohara O . Distinctive four promoters collectively direct expression of brain-derived neurotrophic factor gene. Brain Res Mol Brain Res 1994; 21: 206–218.

    Article  CAS  PubMed  Google Scholar 

  72. Kokaia Z, Metsis M, Kokaia M, Bengzon J, Elmer E, Smith ML et al. Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters. Eur J Neurosci 1994; 6: 587–596.

    Article  CAS  PubMed  Google Scholar 

  73. Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS . Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002; 22: 3251–3261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Vaidya VA, Duman RS . Depression—emerging insights from neurobiology. Br Med Bull 2001; 57: 61–79.

    Article  CAS  PubMed  Google Scholar 

  75. Duman RS . Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 1998; 44: 324–335.

    Article  CAS  PubMed  Google Scholar 

  76. Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT . Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001; 50: 260–265.

    Article  CAS  PubMed  Google Scholar 

  77. Sasaki T, Dai XY, Kuwata S, Fukuda R, Kunugi H, Hattori M et al. Brain-derived neurotrophic factor gene and schizophrenia in Japanese subjects. Am J Med Genet 1997; 74: 443–444.

    Article  CAS  PubMed  Google Scholar 

  78. Hawi Z, Straub RE, O'Neill A, Kendler KS, Walsh D, Gill M et al. No linkage or linkage disequilibrium between brain-derived neurotrophic factor BDNF dinucleotide repeat polymorphism and schizophrenia in Irish families. Psychiatry Res 1998; 81: 111–116.

    Article  CAS  PubMed  Google Scholar 

  79. Wassink TH, Nelson JJ, Crowe RR, Andreasen NC . Heritability of BDNF alleles and their effect on brain morphology in schizophrenia. Am J Med Genet 1999; 88: 724–728.

    Article  CAS  PubMed  Google Scholar 

  80. Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF et al. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 2000; 5: 558–562.

    Article  CAS  PubMed  Google Scholar 

  81. 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  PubMed  Google Scholar 

  82. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. A common mutation in the BDNF gene affects regulated secretion of BDNF, human memory and hippocampal function. Cell 2003; 112: 1–20.

    Article  Google Scholar 

  83. Altar CA, Boylan CB, Fritsche M, Jackson C, Hyman C, Lindsay RM et al. The neurotrophins NT-4/5 and BDNF augment serotonin dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra. Exp Neurol 1994; 130: 31–40.

    Article  CAS  PubMed  Google Scholar 

  84. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtiss G . Psychological Assessment Resources Inc., 1993, pp 26–27.

  85. Webster MJ, Weickert CS, Herman MM, Kleinman JE . BDNF mRNA expression during the postnatal development maturation and aging of the human prefrontal cortex. Brain Res Dev Brain Res 2002; 139: 139–150.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Woo TU, Pucak ML, Kye CH, Matus CV, Lewis DA . Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex. Neuroscience 1997; 80: 1149–1158.

    Article  CAS  PubMed  Google Scholar 

  88. Rosenberg DR, Lewis DA . Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol 1995; 358: 383–400.

    Article  CAS  PubMed  Google Scholar 

  89. Bourgeois JP, Goldman-Rakic PS, Rakic P . Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cerebr Cortex 1994; 4: 78–96.

    Article  CAS  Google Scholar 

  90. Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K et al. The early stages of schizophrenia: speculations on the pathogenesis, pathophysiology, and therapeutic approaches Biol Psychiatry 2001; 50: 884–897.

  91. Molteni R, Lipska BK, Weinberger DR, Racagni G, Riva MA . Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia. Mol Psychiatry 2001; 6: 285–292.

    Article  CAS  PubMed  Google Scholar 

  92. 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  PubMed  Google Scholar 

  93. 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  PubMed  Google Scholar 

  94. Mount HT, Dreyfus CF, Black IB . Neurotrophin-3 selectively increases cultured Purkinje cell survival. Neuroreport 1994; 5: 2497–2500.

    Article  CAS  PubMed  Google Scholar 

  95. Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay RM et al. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  97. 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  PubMed  Google Scholar 

  98. Abe S, Suzuki T, Ito T, Baba A, Hori T, Kurita H et al. Differential expression of GABAA receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration. Synapse 2000; 38: 51–60.

    Article  CAS  PubMed  Google Scholar 

  99. 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. Cerebr Cortex 1995; 5: 550–560.

    Article  CAS  Google Scholar 

  100. Benes F M, Vincent S L, 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  104. 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  PubMed  PubMed Central  Google Scholar 

  105. Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA et al. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cerebr Cortex 2002; 12: 1063–1070.

    Article  Google Scholar 

  106. Ventimiglia R, Mather PE, Jones BE, Lindsay RM . The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur J Neurosci 1995; 7: 213–222.

    Article  CAS  PubMed  Google Scholar 

  107. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 1997; 389: 856–860.

    Article  CAS  PubMed  Google Scholar 

  108. Ivkovic S, Ehrlich ME . Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro. J Neurosci 1999; 19: 5409–5419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 2001; 293: 493–498.

    Article  CAS  PubMed  Google Scholar 

  111. Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350: 230–232.

    Article  CAS  PubMed  Google Scholar 

  112. Zhou J, Bradford HF, Stern GM . The response of human and rat fetal ventral mesencephalon in culture to the brain-derived neurotrophic factor treatment. Brain Res 1994; 656: 147–156.

    Article  CAS  PubMed  Google Scholar 

  113. Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR et al. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 1999; 156: 1580–1589.

    Article  CAS  PubMed  Google Scholar 

  114. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001; 411: 86–89.

    Article  CAS  PubMed  Google Scholar 

  115. Dluzen DE, Gao X, Story GM, Anderson LI, Kucera J, Walro JM et al. Alterations in nigrostriatal dopaminergic function within BDNF mutant mice. Exp Neurol 1999; 160: 500–507.

    Article  CAS  PubMed  Google Scholar 

  116. Dluzen DE et al. Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/− BDNF mutant mice. Exp Neurol 2001; 170: 121–128.

    Article  CAS  PubMed  Google Scholar 

  117. Dluzen DE, Anderson LI, McDermott JL, Kucera J, Walro JM . Striatal dopamine output is compromised within +/− BDNF mice. Synapse 2002; 43: 112–117.

    Article  CAS  PubMed  Google Scholar 

  118. 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  PubMed  Google Scholar 

  119. Eastwood SL, Kerwin RW, Harrison PJ . Immunoautoradiographic evidence for a loss of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-preferring non-N-methyl-D-aspartate glutamate receptors within the medial temporal lobe in schizophrenia. Biol Psychiatry 1997; 41: 636–643.

    Article  CAS  PubMed  Google Scholar 

  120. Noga JT, Hyde TM, Herman MM, Spurney CF, Bigelow LB, Weinberger DR et al. Glutamate receptors in the postmortem striatum of schizophrenic, suicide, and control brains. Synapse 1997; 27: 168–176.

    Article  CAS  PubMed  Google Scholar 

  121. Thakker-Varia S, Alder J, Crozier RA, Plummer MR, Black IB . Rab3A is required for brain-derived neurotrophic factor-induced synaptic plasticity: transcriptional analysis at the population and single-cell levels. J Neurosci 2001; 21: 6782–6790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Blennow K, Bogdanovic N, Heilig M, Grenfeldt B, Karlsson I, Davidsson P et al. Reduction of the synaptic protein rab3a in the thalamus and connecting brain regions in postmortem schizophrenic brains. J Neural Transm 2000; 107: 1085–1097.

    Article  CAS  PubMed  Google Scholar 

  123. Pakkenberg B . Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry 1990; 47: 1023–1028.

    Article  CAS  PubMed  Google Scholar 

  124. Pakkenberg B . The volume of the mediodorsal thalamic nucleus in treated and untreated schizophrenics. Schizophr Res 1992; 7: 95–100.

    Article  CAS  PubMed  Google Scholar 

  125. Popken GJ, Bunney Jr WE, Potkin SG, Jones EG . Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci USA 2000; 97: 9276–9280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Byne W, Buchsbaum MS, Mattiace LA, Hazlett EA, Kemether E, Elhakem SL et al. Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia. Am J Psychiatry 2002; 159: 59–65.

    Article  PubMed  Google Scholar 

  127. Young KA, Manaye KF, Liang C, Hicks PB, German DC . Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 2000; 47: 944–953.

    Article  CAS  PubMed  Google Scholar 

  128. Spalding KL, Tan MM, Hendry IA, Harvey AR . Anterograde transport and trophic actions of BDNF and NT-4/5 in the developing rat visual system. Mol Cell Neurosci 2002; 19: 485–500.

    Article  CAS  PubMed  Google Scholar 

  129. Lotto RB, Asavaritikrai P, Vali L, Price DJ . Target-derived neurotrophic factors regulate the death of developing forebrain neurons after a change in their trophic requirements. J Neurosci 2001; 21: 3904–3910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lewis DA, Cruz DA, Melchitzky DS, Pierri JN . Lamina-specific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus. Am J Psychiatry 2001; 158: 1411–1422.

    Article  CAS  PubMed  Google Scholar 

  131. 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  PubMed  Google Scholar 

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Acknowledgements

We thank Dr David Kaplan for the generous donation of BDNF antibody. We thank our dedicated research assistants who contributed to this work: Robert Fatula, Nader Halim, Deborah Kittell, Davinna Ligons, Benjamin McClintock, and Tara Romanczyk. We also thank those instrumental in the brain collection effort: Juraj Cervenak MD and Yeva Snitkovsky. This work was supported, in part, by a NARSAD young investigator award to CSW.

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Weickert, C., Hyde, T., Lipska, B. et al. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 8, 592–610 (2003). https://doi.org/10.1038/sj.mp.4001308

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  • DOI: https://doi.org/10.1038/sj.mp.4001308

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