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Neural stem cell proliferation is decreased in schizophrenia, but not in depression

Abstract

The phenomenon of adult neurogenesis (AN), that is, the generation of functional neurons from neural stem cells in the dentate gyrus of the hippocampus, has attracted remarkable attention, especially as it was shown that this process is also active in the human brain. Based on animal studies, it has been suggested that reduced AN is implicated in the etiopathology of psychiatric disorders, and that stimulation of AN contributes to the mechanism of action of antidepressant therapies. As data from human post-mortem brain are still lacking, we investigated whether the first step of AN, that is, the level of neural stem cell proliferation (NSP; as quantified by Ki-67 immunohistochemistry), is altered in tissue from the Stanley Foundation Neuropathology Consortium comprising brain specimens from patients with bipolar affective disorder, major depression, schizophrenia as well as control subjects (n=15 in each group). The hypothesis was that stem cell proliferation is reduced in affective disorders, and that antidepressant treatment increases NSP. Neither age, brain weight or pH, brain hemisphere investigated nor duration of storage had an effect on NSP. Only in bipolar disorder, post-mortem interval was a significant intervening variable. In disease, onset of the disorder and its duration likewise did not affect NSP. Also, cumulative lifetime dose of fluphenazine was not correlated with NSP, and presence of antidepressant treatment did not result in an increase of NSP. Concerning the different diagnostic entities, reduced amounts of newly formed cells were found in schizophrenia, but not in major depression. Our findings suggest that reduced NSP may contribute to the pathogenesis of schizophrenia, whereas the rate of NSP does not seem to be critical to the etiopathology of affective disorders, nor is it modified by antidepressant drug treatment.

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References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Duman RS, Malberg J, Nakagawa S . Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 2001; 299: 401–407.

    PubMed  CAS  Google Scholar 

  5. Duman RS . Depression: a case of neuronal life and death? Biol Psychiatry 2004; 56: 140–145.

    Article  Google Scholar 

  6. Benninghoff J, Schmitt A, Mossner R, Lesch KP . When cells become depressed: focus on neural stem cells in novel treatment strategies against depression. J Neural Transm 2002; 109: 947–962.

    Article  CAS  Google Scholar 

  7. Kempermann G, Kronenberg G . Depressed new neurons – adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol Psychiatry 2003; 54: 499–503.

    Article  Google Scholar 

  8. Alonso R, Griebel G, Pavone G, Stemmelin J, Le Fur G, Soubrie P . Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol Psychiatry 2004; 9: 278–286, 224.

    Article  CAS  Google Scholar 

  9. Coe CL, Kramer M, Czeh B, Gould E, Reeves AJ, Kirschbaum C et al. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol Psychiatry 2003; 54: 1025–1034.

    Article  CAS  Google Scholar 

  10. Gould E, Tanapat P . Stress and hippocampal neurogenesis. Biol Psychiatry 1999; 46: 1472–1479.

    Article  CAS  Google Scholar 

  11. Mirescu C, Peters JD, Gould E . Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 2004; 7: 841–846.

    Article  CAS  Google Scholar 

  12. van Praag H, Kempermann G, Gage FH . Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999; 2: 266–270.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Vollmayr B, Simonis C, Weber S, Gass P, Henn F . Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 2003; 54: 1035–1040.

    Article  Google Scholar 

  15. Pham K, Nacher J, Hof PR, McEwen BS . Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci 2003; 17: 879–886.

    Article  Google Scholar 

  16. Reif A, Schmitt A, Fritzen S, Chourbaji S, Bartsch C, Urani A et al. Differential effect of endothelial nitric oxide synthase (NOS-III) on the regulation of adult neurogenesis and behaviour. Eur J Neurosci 2004; 20: 885–895.

    Article  Google Scholar 

  17. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Videbech P, Ravnkilde B . Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004; 161: 1957–1966.

    Article  Google Scholar 

  20. Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 2004; 56: 640–650.

    Article  Google Scholar 

  21. Lucassen PJ, Muller MB, Holsboer F, Bauer J, Holtrop A, Wouda J et al. Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 2001; 158: 453–468.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Curtis MA, Penney EB, Pearson AG, van Roon-Mom WM, Butterworth NJ, Dragunow M et al. Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain. Proc Natl Acad Sci USA 2003; 100: 9023–9027.

    Article  CAS  Google Scholar 

  25. Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 2004; 7: 726–735.

    Article  CAS  Google Scholar 

  26. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci USA 2004; 101: 343–347.

    Article  CAS  Google Scholar 

  27. Kee N, Sivalingam S, Boonstra R, Wojtowicz JM . The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods 2002; 115: 97–105.

    Article  CAS  Google Scholar 

  28. Torrey EF, Webster M, Knable M, Johnston N, Yolken RH . The stanley foundation brain collection and neuropathology consortium. Schizophr Res 2000; 44: 151–155.

    Article  CAS  Google Scholar 

  29. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4: 1313–1317.

    Article  CAS  Google Scholar 

  30. Herrera DG, Yague AG, Johnsen-Soriano S, Bosch-Morell F, Collado-Morente L, Muriach M et al. Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proc Natl Acad Sci USA 2003; 100: 7919–7924.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Ohta Y, Ichimura K . Proliferation markers, proliferating cell nuclear antigen, Ki67, 5-bromo-2′-deoxyuridine, and cyclin D1 in mouse olfactory epithelium. Ann Otol Rhinol Laryngol 2000; 109: 1046–1048.

    Article  CAS  Google Scholar 

  33. Muskhelishvili L, Latendresse JR, Kodell RL, Henderson EB . Evaluation of cell proliferation in rat tissues with BrdU, PCNA, Ki-67(MIB-5) immunohistochemistry and in situ hybridization for histone mRNA. J Histochem Cytochem 2003; 51: 1681–1688.

    Article  CAS  Google Scholar 

  34. Scholzen T, Gerdes J . The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000; 182: 311–322.

    Article  CAS  Google Scholar 

  35. Kuan CY, Schloemer AJ, Lu A, Burns KA, Weng WL, Williams MT et al. Hypoxia–ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. J Neurosci 2004; 24: 10763–10772.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  37. Hellsten J, Wennstrom M, Mohapel P, Ekdahl CT, Bengzon J, Tingstrom A . Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment. Eur J Neurosci 2002; 16: 283–290.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Henn FA, Vollmayr B . Neurogenesis and depression: etiology or epiphenomenon? Biol Psychiatry 2004; 56: 146–150.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Arnold SE, Han LY, Moberg PJ, Turetsky BI, Gur RE, Trojanowski JQ et al. Dysregulation of olfactory receptor neuron lineage in schizophrenia. Arch Gen Psychiatry 2001; 58: 829–835.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Kurtz MM . Neurocognitive impairment across the lifespan in schizophrenia: an update. Schizophr Res 2005; 74: 15–26.

    Article  Google Scholar 

  46. Prickaerts J, Koopmans G, Blokland A, Scheepens A . Learning and adult neurogenesis: survival with or without proliferation? Neurobiol Learn Mem 2004; 81: 1–11.

    Article  Google Scholar 

  47. Kempermann G, Kuhn HG, Gage FH . More hippocampal neurons in adult mice living in an enriched environment. Nature 1997; 386: 493–495.

    Article  CAS  Google Scholar 

  48. Berrettini W . Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet C 2003; 123: 59–64.

    Article  Google Scholar 

  49. Beckmann H, Jakob H . Prenatal disturbances of nerve cell migration in the entorhinal region: a common vulnerability factor in functional psychoses? J Neural Transm Gen Sect 1991; 84: 155–164.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank T Töpner for excellent technical assistance. Post-mortem brain tissue was donated by The Stanley Medical Research Institute Brain Collection, courtesy of Drs Michael B Knable, E Fuller Torrey, Maree J Webster and Robert H Yolken. This study was supported by the Deutsche Forschungsgemeinschaft (Grant RE16321-1 to AR and ML, KFO 1251-1 D to AR and KPL and SFB 581 to KPL), BMBF (IZKF 01 KS 9603) and the European Commission (NEWMOOD LSHM-CT-2003-503474).

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Reif, A., Fritzen, S., Finger, M. et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11, 514–522 (2006). https://doi.org/10.1038/sj.mp.4001791

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