Skip to main content
SpringerLink
Log in

Neurogenesis and schizophrenia: dividing neurons in a divided mind?

European Archives of Psychiatry and Clinical Neuroscience volume 257, pages 290–299 (2007)Cite this article

Abstract

Forty years after the initial discovery of neurogenesis in the postnatal brain of the rat, convincing evidence has been accrued that functional neurons are generated throughout the entire lifespan, particularly in the dentate gyrus (DG) and the subventricular zone (SVZ). This phenomenon has been termed adult neurogenesis (AN) and while it was detected in all examined mammalian species including humans, the physiological role of this process remains unknown. Although a plethora of animal studies indicate an involvement of AN in the pathophysiology of depression, this view has recently kindled considerable controversy. Pertinent studies in humans failed to confirm a role of reduced hippocampal neural stem cell proliferation (NSP) in depression but suggest a contribution to the pathophysiology of schizophrenia. The functional relevance of disturbed AN may encompass erroneous temporal encoding of new memory traces, thereby contributing to cognitive deficits observed in schizophrenia. This AN-hypothesis of schizophrenia is supported by neuroimaging, as well as by several genetically modified rodent models, e.g. reelin and NPAS3 knockout mice. Furthermore, several genes impacting on AN, including NPAS3, were also found to be associated with schizophrenia by case-control studies. In conclusion, several lines of evidence suggest that reduced AN may contribute to the etiopathogenesis of schizophrenic disorders, whereas it does not seem to be a critical risk factor for affective disorders.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1

Abbreviations

AN:

Adult neurogenesis

BDNF:

Brain derived neurotrophic factor

BrdU:

5-bromo-2-deoxyuridine

DG:

Dentate gyrus

DISC1:

Disrupted in schizophrenia 1

ECT:

Electroconvulsive treatment

FGF-2:

Fibroblast growth factor 2

GCL:

Granule cell layer

NMDA:

N-methyl-D-asparate

NO:

Nitric oxide

NOS-I:

Nitric oxide synthase type I (neuronal)

NOS-III:

Nitric oxide synthase type III (endothelial)

NPAS3:

Neuronal PAS domain protein 3

NSP:

Neural stem cell proliferation

OB:

Olfactory bulb

PCP:

Phencyclidine

PPI:

Pre-pulse startle inhibition

SGZ:

Subgranular zone

SVZ:

Subventricular zone

TLE:

Temporal lobe epilepsy

VEGF:

Vascular endothelial growth factor

Wnt:

Wingless-type MMTV integration site family

Wnt 3:

Wnt member 3

References

  1. Aimone JB, Wiles J, Gage FH (2006) Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 9:723–727

    PubMed  CAS  Google Scholar 

  2. Akbarian S, Bunney WE Jr, Potkin SG, Wigal SB, Hagman JO, Sandman CA, Jones EG (1993) Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Arch Gen Psychiatry 50:169–177

    PubMed  CAS  Google Scholar 

  3. Antonova E, Sharma T, Morris R, Kumari V (2004) The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophr Res 70:117–145

    PubMed  Google Scholar 

  4. Arnold SE, Franz BR, Gur RC, Gur RE, Shapiro RM, Moberg PJ, Trojanowski JQ (1995) Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry 152:738–748

    PubMed  CAS  Google Scholar 

  5. Arnold SE, Han LY, Moberg PJ, Turetsky BI, Gur RE, Trojanowski JQ, Hahn CG (2001) Dysregulation of olfactory receptor neuron lineage in schizophrenia. Arch Gen Psychiatry 58:829–835

    PubMed  CAS  Google Scholar 

  6. Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ (2004) Expression of Disrupted-in-schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development. Neuroscience 124:3–10

    PubMed  CAS  Google Scholar 

  7. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998) A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44:88–97

    PubMed  CAS  Google Scholar 

  8. Benes FM, Sorensen I, Bird ED (1991) Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophr Bull 17:597–608

    PubMed  CAS  Google Scholar 

  9. Bernstein HG, Bogerts B, Keilhoff G (2005) The many faces of nitric oxide in schizophrenia. A review. Schizophr Res 78:69–86

    PubMed  Google Scholar 

  10. Bhardwaj RD, Curtis MA, Spalding KL, Buchholz BA, Fink D, Bjork-Eriksson T, Nordborg C, Gage FH, Druid H, Eriksson PS, Frisen J (2006) Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci USA 103:12564–12568

    PubMed  CAS  Google Scholar 

  11. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK (2006) BDNF val66met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59:812–815

    PubMed  CAS  Google Scholar 

  12. Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK (2005) DISC1 and neurocognitive function in schizophrenia. Neuroreport 16:1399–1402

    PubMed  Google Scholar 

  13. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 102:8627–8632

    PubMed  CAS  Google Scholar 

  14. Cameron HA, McEwen BS, Gould E (1995) Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 15:4687–4692

    PubMed  CAS  Google Scholar 

  15. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L (2005) Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 62:1205–1213

    PubMed  CAS  Google Scholar 

  16. Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ (2004) VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36:827–835

    PubMed  CAS  Google Scholar 

  17. Chen J, Park CS, Tang SJ (2006) Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem 281:11910–11916

    PubMed  CAS  Google Scholar 

  18. Cheng A, Wang S, Cai J, Rao MS, Mattson MP (2003) Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol 258:319–333

    PubMed  CAS  Google Scholar 

  19. Ciani E, Severi S, Contestabile A, Bartesaghi R (2004) Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation. J Cell Sci 117:4727–4737

    PubMed  CAS  Google Scholar 

  20. D’Arcangelo G (2006) Reelin mouse mutants as models of cortical development disorders. Epilepsy Behav 8:81–90

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  22. Dawirs RR, Hildebrandt K, Teuchert-Noodt G (1998) Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J Neural Transm 105:317–327

    PubMed  CAS  Google Scholar 

  23. DeLisi LE, Hoff AL (2005) Failure to find progressive temporal lobe volume decreases 10 years subsequent to a first episode of schizophrenia. Psychiatry Res 138:265–268

    PubMed  Google Scholar 

  24. DeLisi LE, Sakuma M, Tew W, Kushner M, Hoff AL, Grimson R (1997) Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res 74:129–140

    PubMed  CAS  Google Scholar 

  25. Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A (2005) Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc Natl Acad Sci USA 102:12578–12583

    PubMed  CAS  Google Scholar 

  26. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269

    PubMed  CAS  Google Scholar 

  27. Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, Diaz-Arrastia R, Brunskill EW, Potter SS, McKnight SL (2004) Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors. Proc Natl Acad Sci USA 101:13648–13653

    PubMed  CAS  Google Scholar 

  28. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317

    PubMed  CAS  Google Scholar 

  29. Fahrner A, Kann G, Flubacher A, Heinrich C, Freiman TM, Zentner J, Frotscher M, Haas CA (2007) Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol 203:320–332

    PubMed  Google Scholar 

  30. Falkai P, Bogerts B (1986) Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236:154–161

    PubMed  CAS  Google Scholar 

  31. Fatemi SH, Earle JA, McMenomy T (2000) Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 5:654–663, 571

    PubMed  CAS  Google Scholar 

  32. Filipkowski RK, Kiryk A, Kowalczyk A, Kaczmarek L (2005) Genetic models to study adult neurogenesis. Acta Biochim Pol 52:359–372

    PubMed  CAS  Google Scholar 

  33. Frotscher M, Haas CA, Forster E (2003) Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold. Cereb Cortex 13:634–640

    PubMed  Google Scholar 

  34. Geuze E, Vermetten E, Bremner JD (2005) MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Mol Psychiatry 10:160–184

    PubMed  CAS  Google Scholar 

  35. Goldman SA, Nottebohm F (1983) Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci USA 80:2390–2394

    PubMed  CAS  Google Scholar 

  36. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E (1997) Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 17:2492–2498

    PubMed  CAS  Google Scholar 

  37. Gould E, Vail N, Wagers M, Gross CG (2001) Adult-generated hippocampal and neocortical neurons in macaques have a transient existence. Proc Natl Acad Sci USA 98:10910–10917

    PubMed  CAS  Google Scholar 

  38. Gratacòs M, González JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X (2007) Brain-derived neurotrophic factor val66met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 61(7):911–922

    PubMed  Google Scholar 

  39. Gray WP, Sundstrom LE (1998) Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790:52–59

    PubMed  CAS  Google Scholar 

  40. Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E (2005) Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci USA 102:9341–9346

    PubMed  CAS  Google Scholar 

  41. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E (2000) Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 57:1061–1069

    PubMed  CAS  Google Scholar 

  42. Halim ND, Weickert CS, McClintock BW, Weinberger DR, Lipska BK (2004) Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 29:1063–1069

    PubMed  CAS  Google Scholar 

  43. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690–6694

    PubMed  CAS  Google Scholar 

  44. Heckers S, Heinsen H, Geiger B, Beckmann H (1991) Hippocampal neuron number in schizophrenia. A stereological study. Arch Gen Psychiatry 48:1002–1008

    PubMed  CAS  Google Scholar 

  45. Heinrich C, Nitta N, Flubacher A, Muller M, Fahrner A, Kirsch M, Freiman T, Suzuki F, Depaulis A, Frotscher M, Haas CA (2006) Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci 26:4701–4713

    PubMed  CAS  Google Scholar 

  46. Hellsten J, Wennstrom M, Bengzon J, Mohapel P, Tingstrom A (2004) Electroconvulsive seizures induce endothelial cell proliferation in adult rat hippocampus. Biol Psychiatry 55:420–427

    PubMed  Google Scholar 

  47. Ho BC, Milev P, O’Leary DS, Librant A, Andreasen NC, Wassink TH (2006) Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor val66met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 63:731–740

    PubMed  CAS  Google Scholar 

  48. Honea R, Crow TJ, Passingham D, Mackay CE (2005) Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am J Psychiatry 162:2233–2245

    PubMed  Google Scholar 

  49. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA 95:15718–15723

    PubMed  CAS  Google Scholar 

  50. Ishizuka K, Paek M, Kamiya A, Sawa A (2006) A review of disrupted-in-schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol Psychiatry 59:1189–1197

    PubMed  CAS  Google Scholar 

  51. Jeong SH, Joo EJ, Ahn YM, Lee KY, Kim YS (2006) Investigation of genetic association between human Frizzled homolog 3 gene (FZD3) and schizophrenia: results in a Korean population and evidence from meta-analysis. Psychiatry Res 143:1–11

    PubMed  CAS  Google Scholar 

  52. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950

    PubMed  CAS  Google Scholar 

  53. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 7:1167–1178

    PubMed  Google Scholar 

  54. Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M, Cascio MB, Elashvili S, Koizumi H, Takanezawa Y, Dickerson F, Yolken R, Arai H, Sawa A (2006) DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet 15:3313–3323

    PubMed  CAS  Google Scholar 

  55. Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW (2003) Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet 40:325–332

    PubMed  CAS  Google Scholar 

  56. Keilhoff G, Bernstein HG, Becker A, Grecksch G, Wolf G (2004) Increased neurogenesis in a rat ketamine model of schizophrenia. Biol Psychiatry 56:317–322

    PubMed  CAS  Google Scholar 

  57. Kempermann G (2002) Why new neurons? Possible functions for adult hippocampal neurogenesis. J Neurosci 22:635–638

    PubMed  CAS  Google Scholar 

  58. Kim HM, Qu T, Kriho V, Lacor P, Smalheiser N, Pappas GD, Guidotti A, Costa E, Sugaya K (2002) Reelin function in neural stem cell biology. Proc Natl Acad Sci USA 99:4020–4025

    PubMed  CAS  Google Scholar 

  59. Kippin TE, Kapur S, van der Kooy D (2005) Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 25:5815–5823

    PubMed  CAS  Google Scholar 

  60. Kitamura T, Mishina M, Sugiyama H (2006) Dietary restriction increases hippocampal neurogenesis by molecular mechanisms independent of NMDA receptors. Neurosci Lett 393:94–96

    PubMed  CAS  Google Scholar 

  61. Kitamura T, Mishina M, Sugiyama H (2003) Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit. Neurosci Res 47:55–63

    PubMed  CAS  Google Scholar 

  62. Kitamura T, Sugiyama H (2006) Running wheel exercises accelerate neuronal turnover in mouse dentate gyrus. Neurosci Res 56:45–52

    PubMed  CAS  Google Scholar 

  63. Knable MB, Barci BM, Webster MJ, Meador-Woodruff J, Torrey EF (2004) Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol Psychiatry 9:609–620, 544

    PubMed  CAS  Google Scholar 

  64. Kodama M, Fujioka T, Duman RS (2004) Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 56:570–580

    PubMed  CAS  Google Scholar 

  65. Kovelman JA, Scheibel AB (1984) A neurohistological correlate of schizophrenia. Biol Psychiatry 19:1601–1621

    PubMed  CAS  Google Scholar 

  66. Lamont SR, Stanwell BJ, Hill R, Reid IC, Stewart CA (2005) Ketamine pre-treatment dissociates the effects of electroconvulsive stimulation on mossy fibre sprouting and cellular proliferation in the dentate gyrus. Brain Res 1053:27–32

    PubMed  CAS  Google Scholar 

  67. Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375

    PubMed  CAS  Google Scholar 

  68. Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:1370–1375

    PubMed  CAS  Google Scholar 

  69. Liu J, Suzuki T, Seki T, Namba T, Tanimura A, Arai H (2006) Effects of repeated phencyclidine administration on adult hippocampal neurogenesis in the rat. Synapse 60:56–68

    PubMed  CAS  Google Scholar 

  70. Lucassen PJ, Muller MB, Holsboer F, Bauer J, Holtrop A, Wouda J, Hoogendijk WJ, De Kloet ER, Swaab DF (2001) Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 158:453–468

    PubMed  CAS  Google Scholar 

  71. Macintyre G, Alford T, Xiong L, Rouleau GA, Tibbo P, Cox DW (2006) A neuronal PAS gene, NPAS3, is a candidate for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 141B:P268

    Google Scholar 

  72. Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingstrom A (2000) Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 47:1043–1049

    PubMed  CAS  Google Scholar 

  73. Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110

    PubMed  CAS  Google Scholar 

  74. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9:1415–1423

    PubMed  CAS  Google Scholar 

  75. Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T, Kuroda S, Katayama T, Tohyama M (2003) Disrupted-in-schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 8:685–694

    PubMed  CAS  Google Scholar 

  76. Moghaddam B (2003) Bringing order to the glutamate chaos in schizophrenia. Neuron 40:881–884

    PubMed  CAS  Google Scholar 

  77. Moreno-Lopez B, Romero-Grimaldi C, Noval JA, Murillo-Carretero M, Matarredona ER, Estrada C (2004) Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J Neurosci 24:85–95

    PubMed  CAS  Google Scholar 

  78. Muller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ, Holsboer F, Swaab DF (2001) Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci 14:1603–1612

    PubMed  CAS  Google Scholar 

  79. Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 23:10841–10851

    PubMed  CAS  Google Scholar 

  80. O’Tuathaigh CM, Babovic D, O’Meara G, Clifford JJ, Croke DT, Waddington JL (2007) Susceptibility genes for schizophrenia: Characterisation of mutant mouse models at the level of phenotypic behaviour. Neurosci Biobehav Rev 31:60–78

    PubMed  CAS  Google Scholar 

  81. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, Okawa M, Yamada N, Hatten ME, Snyder SH, Ross CA, Sawa A (2003) Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 100:289–294

    PubMed  CAS  Google Scholar 

  82. Packer MA, Stasiv Y, Benraiss A, Chmielnicki E, Grinberg A, Westphal H, Goldman SA, Enikolopov G (2003) Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci USA 100:9566–9571

    PubMed  CAS  Google Scholar 

  83. Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494

    PubMed  CAS  Google Scholar 

  84. Park C, Kang M, Kim-Kwon Y, Kim J, Ahn H, Huh Y (2002) Inhibition of neuronal nitric oxide synthase increases adrenalectomy-induced granule cell death in the rat dentate gyrus. Brain Res 933:81–84

    PubMed  CAS  Google Scholar 

  85. Park C, Kang M, Kwon YK, Chung JH, Ahn H, Huh Y (2001) Inhibition of neuronal nitric oxide synthase enhances cell proliferation in the dentate gyrus of the adrenalectomized rat. Neurosci Lett 309:9–12

    PubMed  CAS  Google Scholar 

  86. Park C, Sohn Y, Shin KS, Kim J, Ahn H, Huh Y (2003) The chronic inhibition of nitric oxide synthase enhances cell proliferation in the adult rat hippocampus. Neurosci Lett 339:9–12

    PubMed  CAS  Google Scholar 

  87. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24:10099–10102

    PubMed  CAS  Google Scholar 

  88. Pickard B, Christoforou A, Thomason P, Evans K, Morris S, Porteus D, Blackwood D, Muir W (2006) A case-control association study on the NPAS3 gene. Am J Med Genet B Neuropsychiatr Genet 141B:P100

    Google Scholar 

  89. Pickard BS, Pieper AA, Porteous DJ, Blackwood DH, Muir WJ (2006) The NPAS3 gene–emerging evidence for a role in psychiatric illness. Ann Med 38:439–448

    PubMed  CAS  Google Scholar 

  90. Pieper AA, Wu X, Han TW, Estill SJ, Dang Q, Wu LC, Reece-Fincanon S, Dudley CA, Richardson JA, Brat DJ, McKnight SL (2005) The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc Natl Acad Sci USA 102: 14052–14057

    PubMed  CAS  Google Scholar 

  91. Podhorna J, Didriksen M (2004) The heterozygous reeler mouse: behavioural phenotype. Behav Brain Res 153:43–54

    PubMed  CAS  Google Scholar 

  92. Porteous DJ, Thomson P, Brandon NJ, Millar JK (2006) The genetics and biology of DISC1–an emerging role in psychosis and cognition. Biol Psychiatry 60:123–131

    PubMed  CAS  Google Scholar 

  93. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP (2006) Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11:514–522

    PubMed  CAS  Google Scholar 

  94. Reif A, Herterich S, Strobel A, Ehlis AC, Saur D, Jacob CP, Wienker T, Topner T, Fritzen S, Walter U, Schmitt A, Fallgatter AJ, Lesch KP (2006) A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function. Mol Psychiatry 11:286–300

    PubMed  CAS  Google Scholar 

  95. Reif A, Schmitt A, Fritzen S, Chourbaji S, Bartsch C, Urani A, Wycislo M, Mossner R, Sommer C, Gass P, Lesch KP (2004) Differential effect of endothelial nitric oxide synthase (NOS-III) on the regulation of adult neurogenesis and behaviour. Eur J Neurosci 20:885–895

    PubMed  Google Scholar 

  96. Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25:1089–1094

    PubMed  CAS  Google Scholar 

  97. Schanzer A, Wachs FP, Wilhelm D, Acker T, Cooper-Kuhn C, Beck H, Winkler J, Aigner L, Plate KH, Kuhn HG (2004) Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol 14:237–248

    Article  PubMed  Google Scholar 

  98. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192:348–356

    PubMed  CAS  Google Scholar 

  99. Schmitt A, Fendt M, Zink M, Ebert U, Starke M, Berthold M, Herb A, Petroianu G, Falkai P, Henn FA (2007) Altered NMDA receptor expression and behavior following postnatal hypoxia: potential relevance to schizophrenia. J Neural Transm 114:239–248

    PubMed  CAS  Google Scholar 

  100. Schmitt A, Weber S, Jatzko A, Braus DF, Henn FA (2004) Hippocampal volume and cell proliferation after acute and chronic clozapine or haloperidol treatment. J Neural Transm 111:91–100

    PubMed  CAS  Google Scholar 

  101. Schurov IL, Handford EJ, Brandon NJ, Whiting PJ (2004) Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry 9:1100–1110

    PubMed  CAS  Google Scholar 

  102. Scott BW, Wojtowicz JM, Burnham WM (2000) Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Exp Neurol 165:231–236

    PubMed  CAS  Google Scholar 

  103. Song HJ, Stevens CF, Gage FH (2002) Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci 5:438–445

    PubMed  CAS  Google Scholar 

  104. Stanfield BB, Cowan WM (1979) The development of the hippocampus and dentate gyrus in normal and reeler mice. J Comp Neurol 185:423–459

    PubMed  CAS  Google Scholar 

  105. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA (2006) Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry 188:510–518

    PubMed  Google Scholar 

  106. Suzuki M, Nelson AD, Eickstaedt JB, Wallace K, Wright LS, Svendsen CN (2006) Glutamate enhances proliferation and neurogenesis in human neural progenitor cell cultures derived from the fetal cortex. Eur J Neurosci 24:645–653

    PubMed  Google Scholar 

  107. Sweatt JD (2004) Hippocampal function in cognition. Psychopharmacology (Berl) 174:99–110

    CAS  Google Scholar 

  108. Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, Goldman D, Malhotra AK (2005) Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 10:631–636

    PubMed  CAS  Google Scholar 

  109. Toro CT, Deakin JF (2007) Adult neurogenesis and schizophrenia: a window on abnormal early brain development? Schizophr Res 90:1–14

    PubMed  CAS  Google Scholar 

  110. Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tueting P, Sharma R, Grayson DR, Costa E, Guidotti A (2002) An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci USA 99:17095–17100

    PubMed  CAS  Google Scholar 

  111. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034

    PubMed  Google Scholar 

  112. Wakade CG, Mahadik SP, Waller JL, Chiu FC (2002) Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 69:72–79

    PubMed  CAS  Google Scholar 

  113. Walker MA, Highley JR, Esiri MM, McDonald B, Roberts HC, Evans SP, Crow TJ (2002) Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia. Am J Psychiatry 159:821–828

    PubMed  Google Scholar 

  114. Wang HD, Dunnavant FD, Jarman T, Deutch AY (2004) Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 29:1230–1238

    PubMed  CAS  Google Scholar 

  115. Won SJ, Kim SH, Xie L, Wang Y, Mao XO, Jin K, Greenberg DA (2006) Reelin-deficient mice show impaired neurogenesis and increased stroke size. Exp Neurol 198:250–259

    PubMed  CAS  Google Scholar 

  116. Zhang R, Zhang L, Zhang Z, Wang Y, Lu M, Lapointe M, Chopp M (2001) A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 50:602–611

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, Julius-Maximilians-University Würzburg, Füchsleinstr. 15, 97080, Würzburg, Germany

    Andreas Reif, Angelika Schmitt, Sabrina Fritzen & Klaus-Peter Lesch

Authors
  1. Andreas Reif
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angelika Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sabrina Fritzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Klaus-Peter Lesch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Reif.

Additional information

The work of the authors is supported by the Deutsche Forschungsgemeinschaft (Grant RE1632/1–1 and 1–3 to A.R., KFO 125/1–1 D to A.R. and K.P.L., and SFB 581 to K.P.L.), BMBF (IZKF 01 KS 9603) and the European Commission (NEWMOOD LSHM-CT-2003-503474).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reif, A., Schmitt, A., Fritzen, S. et al. Neurogenesis and schizophrenia: dividing neurons in a divided mind?. Eur Arch Psychiatry Clin Neurosc 257, 290–299 (2007). https://doi.org/10.1007/s00406-007-0733-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00406-007-0733-3

Keywords

search

Navigation