Bernhard Bogerts

Esther Stürze

Hans-Gert Bernstein

HRČAK - Portal of Croatian Scientific and Professional Journals

Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 33H. G. Bernstein et al. Cell cycle disturbances in schizophreniaWORKSHOP: CELL CYCLE ABNORMALITIES IN SCHIZOPHRENIACELL CYCLE DISTURBANCES IN SCHIZOPHRENIA:THE JOURNEY SO FARHans-Gert Bernstein, Esther Stürze, Bernhard BogertsDepartment of Psychiatry, University of MagdeburgDepartment of Psychiatry, University of Magdeburg Leipziger Str. 44, D-39120 Magdeburg, GermanyAbstractAs an introduction to the Pula Workshop „Schizo-phrenia and Cell Cycle Disturbances“, we give a short survey on the current knowledge about the impact of cell cycle disturbances in schizophrenia. While the ex-istence of reduced adult neurogenesis in schizophrenia is supported by various studies, less is known about such disturbances in non-neural cells (for example, in oligodendrocytes). We herein try to show that both impaired neuronal and oligodendroglial cell cycles might contribute to the pathophysiology of schizo-phrenia, and that  antipsychotic treatment might be a way to „normalize“ cell cycle abnormalities.Schizophrenia is a chronic and disabling mental illness aff ecting several millions of people worldwide. Th e etiopathogenesis of the disease, however, remains enigmatic, and various competing hypotheses have been proposed to explain its origin. Amongst these, the proposition that schizophrenia may have its roots in early brain development has gained much attention. During the past decade the scientifi c community has witnessed a considerable progress in the understand-ing of  normal neural development and neurogenesis, and convincing evidence has accumulated in favour of  abberant neurodeveloment in schizophrenia1. Th is neurodevelopmental theory, however, leaves some vital questions unanswered. For example, how can a purely neurodevelopmental disorder manifest for the fi rst time in an adolescent or an adult2? It soon became clear that certain „disease-shaping“ pathomechanisms must still be active in the adult human brain, which contribute to the development and/or progression of the disease. So far, mainly neurodegenerative and im-mune processes have been blamed to be responsible for this3.Why do we assume that cell cycle disturbances may be of relevance for  schizophrenia?Th e discovery of neurogenesis in the postnatal brain has added a new, intruiging aspect to the discussion about the origin of schizophrenia. It is now beyond any doubt that in circumscribed brains areas, particu-larly in the dentate gyrus and the subventricular zone, functional neurons are generated throughout the en-tire lifespan4. Th is phenomenon has been termed adult neurogenesis. Although the actual physiological role of this process remains largely unknown, ist function-ing is obviously necessary to maintain normal brain function. Hence, disturbancees of adult neurogenen-sis (or, more precisely, neural stem cell proliferation) might signifi cantly contribute to neuropsychiatric disorders, including schizophrenia. Indeed, numerous animal studies and investigations in humans give now reason to suppose that decreased, and not increased5, hippocampal cell proliferation may be part of the pathophysiology of schizophrenia. Th is reduced birth of new neurons may contribute to to disease-related smaller hippocampal volumes, considerable cognitive defi cits as well as to delusions and hallucinations6.H. G. Bernstein et al. Cell cycle disturbances in schizophrenia34 Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010How is the cell cycle controlled, and do the controlling agents show abnormal levels in schizophrenia?Little is currently known about cell cycle regulat-ing proteins in the adult hippocampus and other brain areas. In all mammalian cells including neural stem cells, cellular proliferation is mainly controlled during the G1 phase of the cell cycle. Cyclins are cell cycle proteins known to be positive regulators of the cell cycle. Th e cyclins D and E are present in the adult subgranular zone and hippocampus7. Both cyclins D1 and D2 have been found upregulated in schizophre-nia (8, 9). Interestingly, cyclin D2 was identifi ed as a part of the regulatory network of glutamic acid decar-boxylase (GAD67), an enzyme which is profoundly dysregulated in schizophrenia8.Cyclin-dependent kinases, which control the cell cycle by negatively regulating cell cycle progression, which are. expressed in proliferating neural stem cells, are reduced in their expression in schizophrenia8,10. In addition, intracerebroventricular infusion of a non-selective cyclin-dependent kinase inhibitors de-creases cell proliferation in the subgranular zone in rats11. Furthermore, the suppression of the expression of the gene Disrupted-in-Schizophrenia 1 (DISC 1) was shown to strongly reduce neural progenitor pro-liferation, leading to premature cell cycle exit and dif-ferentiation. DISC1 mediates this function by regu-lating glycogen synthase kinase-3 beta12. Th is might be of considerable importance for our understanding of schizophrenia, since DISC1 has repeatedly been linked with the disease. Lastly, adult neurogenesis is under control of neurotrophic factors, most of which are known to be altered in their expression in schizo-phrenia13.Does antipsychotic treatment „normalize“ the cell cycle disturbances  in schizophrenia?Initially, reduced neurogenesis was detected in postmortem hippocampi of neuroleptic- treated, chronic schizophrenics6,14, So, the spontaneous an-swer to this question would be a clear „No“. In sup-port of this failure,  results from animal studies could be taken that show unchanged levels of stem cell proliferation after haloperidol treatment. One study, however, demonstrated an increase in adult neurogen-esis upon treatment. In two studies it was found that chronic treatment with the atypical antipsychotic clo-zapine does not infl uence proliferation or survival of newborn cells in the hippocampal dentat gyrus, while acute adminstration doubled the number of BrdU-incorporating cells. Results with olanzapine are also contradictory (reviewed in ref. 6). Our group could show that repeated application of subanesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine, which has been shown to mimic model aspects of schizophrenia in animals, stimulates the hippocampal neurogenesis15, and that both halo-peridol and risperidone promote stem cell survival in rats (16, and this symposium). Th us, further research is needed in order to get more conclusive answers as to whether or not antipsychotic treatment is helpful in „normalizing“ cell cycle in schizophrenia (see also below).Abnormal cell cycles and schizophrenia – is it all with the neurons?Th e fascination of adult neurogenesis and ist pos-sible disturbances in schizophrenia should not allow us to obscure our view of non-neural types in the brain, namely oligodendroglial cells. Schizophrenia is increasingly conceptualised as an illness of disturbed functional circuitry, and a wide range of white mat-ter abnormalities have been revealed in schizophre-nia. Th ese include volume reductions, hypodensities, myelination defects, and especially alterations of den-sity, morphology and gene expression profi les of the myelin-forming cells, oligodendrocytes and their pro-genitors (for recent review see ref. 17).Th ere are numerous reports about reduced oligo-dendrocyte density in schizophrenia, which may re-sult from impaired mitoses of these cells. However, there is yet only circumstantial evidence in favour of disease-related oligodendrocyte cycle abnormalities in schizophrenia. In a recent, comprehensive analy-sis Katsel and colleagues9 found that eight cell-cycle related antigens (including cyclins D1 and D2) are upregulated, and nine other antigens (indluding cy-clin-dependent kinase inhibitors) are down-regulated in OLs isolated from postmortem brains of schizo-phrenics. Remarkably, the expression diff erences were more pronounced in anti-psychotic medication free patients with schizophrenia than in treated ones. Th e authors conclude that the normal patterns of Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 35H. G. Bernstein et al. Cell cycle disturbances in schizophreniacell cycle gen and protein expression is disrupted in schizophrenia, and that this disruption may signifi -cantly contribute to oligodendroglial defi cits observed in schizophrenia. In this study,  a near-signifi cant change was observed for prohibitin, a mitochondrial protein which is prominently involved in cell cycle control18. Th e number of prohibitin expressing neu-rons19 and oligodendrocytes (this symposium) is in-creased  in schizophrenia. It should be emphasized, however, that prohibitin is expressed in immature and mature (postmitotic) OLs . Th us, a possible infl uence of prohibitin on the cell cycle is by far not the only function of this multi-talented protein, which may be compromised in schizophrenia..In sum, it becomes obvious that cell cycle distur-bances are possibly not restricted to neurons, but might be a general phenomenon in schizophrenia20, which deserves much more attention in future research.References1.  WEINBERGER DR. On the plausibility of “the neurode-velopmental hypothesis” of schizophrenia. Neuropsychop-harmacology 1996; 14(3 Suppl):1S-11S.2. GUPTA S, KULHARA P. What is schizophrenia: A neurode-velopmental or neurodegenerative disorder or a combination of both? A critical analysis. Indian J Psychiatry 2010; 52: 21-27.3. CANNON TD. What is the role of theories in the study of schizophrenia? Schizophr Bull. 25; 35:563-567. 4. MA DK, BONAGUIDI MA, MING GL, SONG H. Adult neural stem cells in the mammalian central nervous system. Cell Res. 2009;19:672-682.5. NISHIOKA N, ARNOLD SE. Evidence for oxidative DNA damage in the hippocampus of elderly patients with chronic schizophrenia. Am J Geriatr Psychiatry. 2004;12:167-175.6. REIF A, SCHMITT A, FRITZEN S, LESCH KP. Neuro-genesis and schizophrenia: dividing neurons in a divided mind? Eur Arch Psychiatry Clin Neurosci. 2007;257:290-299.7. HEINE VM, MASLAM S, JOËLS M, LUCASSEN PJ. Increased P27KIP1 protein expression in the dentate gyrus of chronically stressed rats indicates G1 arrest involvement. Neuroscience. 2004;129:593-601.8. Benes FM. Relationship of GAD67 regulation to cell cycle and DANN repair in GABA neurons in the adult hippocam-pus. Cell Cycle 2010;9:1-3.9. KATSEL P, DAVIS KL, LI C, TAN W, Greenstein E, Kleiner Hoff man LB, Haroutuian V. Abnormal indices of cell cycle activity in schizphrenia in association with oligo-dendrocytes. Neuropsychopharmacology 2008; 33: 2993-3009.10. HAYES TE, VALTZ NL, MCKAY RD. Downregulation of CDC2 upon terminal diff erentiation  of neurons. New Biol. 1991; 3:259-269.11. MAĆKOWIAK M, KOLASIEWICZ W, MARKOWICZKULA K, WEDZONY K. Purvalanol A, inhibitor of cyclin-dependent kinases attenuates proliferation of cells in the dentate gyrus of the adult rat hippocampus Pharmacol Rep. 2005; 57:845-849.12. MAO Y, GE X, FRANK CL, MADISON JM, KOEHLER AN, DOUD MK, TASSA C, BERRY EM, SODA T, SINGH KK, BIECHELE T, PETRYSHEN TL, MOON RT, HAGGARTY SJ, TSAI LH. Disrupted in schizophre-nia 1 regulates neuronal progenitor proliferation via modula-tion of GSK3beta/beta-catenin signaling. Cell. 20;136:1017-1031.13. BATH KG, LEE FS. Neurotrophic factor control of adult SVZ neurogenesis. Dev Neurobiol. 2010 Feb 22. [Epub ahead of print].14. REIF A, FRITZEN S, FINGER M, STROBEL A, LAUER M, SCHMITT A, LESCH KP. Neural stem cell prolif-eration is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006; 11:514-22.15. KEILHOFF G, BERNSTEIN HG, BECKER A, GRECKSCH G, WOLF G. Increased neurogenesis in a rat ketamine model of schizophrenia. Biol Psychiatry. 2004; 56: 317-322.16. KEILHOFF G, GRECKSCH G, BERNSTEIN HG, ROSKODEN T, BECKER A. Risperidone and haloperidol promote survival of stem cells in the rat hippocampus. Eur Arch Psychiatr Clin Neurosci 2010; 260:151-162. 17. BERNSTEIN HG, STEINER J, BOGERTS B. Glial cells in schizophrenia: pathophysiological signifi cance and possi-ble consequences for therapy. Expert Rev Neurother. 2009; 9:1059-1071.18. MERKWIRTH C, DARGAZANLI S, TATSUTA T, GEIMER S, LÖWER B, WUNDERLICH FT, VON KLEISTRETZOW JC, WESTERMANN B, LANGER T. Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mito-cheondria. Genes Dev. 2008;22, 476-488.19. SMALLA KH, MIKHAYLOVA M, SAHIN J, BERNSTEIN HG, BOGERTS B, SCHMITT A, VAN DER SCHORS R, SMIT AB, LI KW, GUNDELFINGER ED, KREUTZ MR. A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia. Mol Psychiatry. 2008; 13:878-896. 20. WANG L, LOCKSTONE HE, GUEST PC, LEVIN Y, PALOTÁS A, PIETSCH S, SCHWARZ E, RAHMOUNE R, HARRIS LW, MA D, BAHN S. Expression profi ling of fi broblasts identifi es cell cycle abnormalities in schizophrenia. J Proteome Res. 2010; 9:521-527.

English

Cell Cycle Disturbances in Schizophrenia: The Journey So Far

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Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 33H. G. Bernstein et al. Cell cycle disturbances in schizophreniaWORKSHOP: CELL CYCLE ABNORMALITIES IN SCHIZOPHRENIACELL CYCLE DISTURBANCES IN SCHIZOPHRENIA:THE JOURNEY SO FARHans-Gert Bernstein, Esther Stürze, Bernhard BogertsDepartment of Psychiatry, University of MagdeburgDepartment of Psychiatry, University of Magdeburg Leipziger Str. 44, D-39120 Magdeburg, GermanyAbstractAs an introduction to the Pula Workshop „Schizo-phrenia and Cell Cycle Disturbances“, we give a short survey on the current knowledge about the impact of cell cycle disturbances in schizophrenia. While the ex-istence of reduced adult neurogenesis in schizophrenia is supported by various studies, less is known about such disturbances in non-neural cells (for example, in oligodendrocytes). We herein try to show that both impaired neuronal and oligodendroglial cell cycles might contribute to the pathophysiology of schizo-phrenia, and that  antipsychotic treatment might be a way to „normalize“ cell cycle abnormalities.Schizophrenia is a chronic and disabling mental illness aﬀ ecting several millions of people worldwide. Th e etiopathogenesis of the disease, however, remains enigmatic, and various competing hypotheses have been proposed to explain its origin. Amongst these, the proposition that schizophrenia may have its roots in early brain development has gained much attention. During the past decade the scientiﬁ c community has witnessed a considerable progress in the understand-ing of  normal neural development and neurogenesis, and convincing evidence has accumulated in favour of  abberant neurodeveloment in schizophrenia1. Th is neurodevelopmental theory, however, leaves some vital questions unanswered. For example, how can a purely neurodevelopmental disorder manifest for the ﬁ rst time in an adolescent or an adult2? It soon became clear that certain „disease-shaping“ pathomechanisms must still be active in the adult human brain, which contribute to the development and/or progression of the disease. So far, mainly neurodegenerative and im-mune processes have been blamed to be responsible for this3.Why do we assume that cell cycle disturbances may be of relevance for  schizophrenia?Th e discovery of neurogenesis in the postnatal brain has added a new, intruiging aspect to the discussion about the origin of schizophrenia. It is now beyond any doubt that in circumscribed brains areas, particu-larly in the dentate gyrus and the subventricular zone, functional neurons are generated throughout the en-tire lifespan4. Th is phenomenon has been termed adult neurogenesis. Although the actual physiological role of this process remains largely unknown, ist function-ing is obviously necessary to maintain normal brain function. Hence, disturbancees of adult neurogenen-sis (or, more precisely, neural stem cell proliferation) might signiﬁ cantly contribute to neuropsychiatric disorders, including schizophrenia. Indeed, numerous animal studies and investigations in humans give now reason to suppose that decreased, and not increased5, hippocampal cell proliferation may be part of the pathophysiology of schizophrenia. Th is reduced birth of new neurons may contribute to to disease-related smaller hippocampal volumes, considerable cognitive deﬁ cits as well as to delusions and hallucinations6.H. G. Bernstein et al. Cell cycle disturbances in schizophrenia34 Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010How is the cell cycle controlled, and do the controlling agents show abnormal levels in schizophrenia?Little is currently known about cell cycle regulat-ing proteins in the adult hippocampus and other brain areas. In all mammalian cells including neural stem cells, cellular proliferation is mainly controlled during the G1 phase of the cell cycle. Cyclins are cell cycle proteins known to be positive regulators of the cell cycle. Th e cyclins D and E are present in the adult subgranular zone and hippocampus7. Both cyclins D1 and D2 have been found upregulated in schizophre-nia (8, 9). Interestingly, cyclin D2 was identiﬁ ed as a part of the regulatory network of glutamic acid decar-boxylase (GAD67), an enzyme which is profoundly dysregulated in schizophrenia8.Cyclin-dependent kinases, which control the cell cycle by negatively regulating cell cycle progression, which are. expressed in proliferating neural stem cells, are reduced in their expression in schizophrenia8,10. In addition, intracerebroventricular infusion of a non-selective cyclin-dependent kinase inhibitors de-creases cell proliferation in the subgranular zone in rats11. Furthermore, the suppression of the expression of the gene Disrupted-in-Schizophrenia 1 (DISC 1) was shown to strongly reduce neural progenitor pro-liferation, leading to premature cell cycle exit and dif-ferentiation. DISC1 mediates this function by regu-lating glycogen synthase kinase-3 beta12. Th is might be of considerable importance for our understanding of schizophrenia, since DISC1 has repeatedly been linked with the disease. Lastly, adult neurogenesis is under control of neurotrophic factors, most of which are known to be altered in their expression in schizo-phrenia13.Does antipsychotic treatment „normalize“ the cell cycle disturbances  in schizophrenia?Initially, reduced neurogenesis was detected in postmortem hippocampi of neuroleptic- treated, chronic schizophrenics6,14, So, the spontaneous an-swer to this question would be a clear „No“. In sup-port of this failure,  results from animal studies could be taken that show unchanged levels of stem cell proliferation after haloperidol treatment. One study, however, demonstrated an increase in adult neurogen-esis upon treatment. In two studies it was found that chronic treatment with the atypical antipsychotic clo-zapine does not inﬂ uence proliferation or survival of newborn cells in the hippocampal dentat gyrus, while acute adminstration doubled the number of BrdU-incorporating cells. Results with olanzapine are also contradictory (reviewed in ref. 6). Our group could show that repeated application of subanesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine, which has been shown to mimic model aspects of schizophrenia in animals, stimulates the hippocampal neurogenesis15, and that both halo-peridol and risperidone promote stem cell survival in rats (16, and this symposium). Th us, further research is needed in order to get more conclusive answers as to whether or not antipsychotic treatment is helpful in „normalizing“ cell cycle in schizophrenia (see also below).Abnormal cell cycles and schizophrenia – is it all with the neurons?Th e fascination of adult neurogenesis and ist pos-sible disturbances in schizophrenia should not allow us to obscure our view of non-neural types in the brain, namely oligodendroglial cells. Schizophrenia is increasingly conceptualised as an illness of disturbed functional circuitry, and a wide range of white mat-ter abnormalities have been revealed in schizophre-nia. Th ese include volume reductions, hypodensities, myelination defects, and especially alterations of den-sity, morphology and gene expression proﬁ les of the myelin-forming cells, oligodendrocytes and their pro-genitors (for recent review see ref. 17).Th ere are numerous reports about reduced oligo-dendrocyte density in schizophrenia, which may re-sult from impaired mitoses of these cells. However, there is yet only circumstantial evidence in favour of disease-related oligodendrocyte cycle abnormalities in schizophrenia. In a recent, comprehensive analy-sis Katsel and colleagues9 found that eight cell-cycle related antigens (including cyclins D1 and D2) are upregulated, and nine other antigens (indluding cy-clin-dependent kinase inhibitors) are down-regulated in OLs isolated from postmortem brains of schizo-phrenics. Remarkably, the expression diﬀ erences were more pronounced in anti-psychotic medication free patients with schizophrenia than in treated ones. Th e authors conclude that the normal patterns of Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 35H. G. Bernstein et al. Cell cycle disturbances in schizophreniacell cycle gen and protein expression is disrupted in schizophrenia, and that this disruption may signiﬁ -cantly contribute to oligodendroglial deﬁ cits observed in schizophrenia. In this study,  a near-signiﬁ cant change was observed for prohibitin, a mitochondrial protein which is prominently involved in cell cycle control18. Th e number of prohibitin expressing neu-rons19 and oligodendrocytes (this symposium) is in-creased  in schizophrenia. It should be emphasized, however, that prohibitin is expressed in immature and mature (postmitotic) OLs . Th us, a possible inﬂ uence of prohibitin on the cell cycle is by far not the only function of this multi-talented protein, which may be compromised in schizophrenia..In sum, it becomes obvious that cell cycle distur-bances are possibly not restricted to neurons, but might be a general phenomenon in schizophrenia20, which deserves much more attention in future research.References1.  WEINBERGER DR. On the plausibility of “the neurode-velopmental hypothesis” of schizophrenia. Neuropsychop-harmacology 1996; 14(3 Suppl):1S-11S.2. GUPTA S, KULHARA P. What is schizophrenia: A neurode-velopmental or neurodegenerative disorder or a combination of both? A critical analysis. Indian J Psychiatry 2010; 52: 21-27.3. CANNON TD. What is the role of theories in the study of schizophrenia? Schizophr Bull. 25; 35:563-567. 4. MA DK, BONAGUIDI MA, MING GL, SONG H. Adult neural stem cells in the mammalian central nervous system. Cell Res. 2009;19:672-682.5. NISHIOKA N, ARNOLD SE. Evidence for oxidative DNA damage in the hippocampus of elderly patients with chronic schizophrenia. Am J Geriatr Psychiatry. 2004;12:167-175.6. REIF A, SCHMITT A, FRITZEN S, LESCH KP. Neuro-genesis and schizophrenia: dividing neurons in a divided mind? Eur Arch Psychiatry Clin Neurosci. 2007;257:290-299.7. HEINE VM, MASLAM S, JOËLS M, LUCASSEN PJ. Increased P27KIP1 protein expression in the dentate gyrus of chronically stressed rats indicates G1 arrest involvement. Neuroscience. 2004;129:593-601.8. Benes FM. Relationship of GAD67 regulation to cell cycle and DANN repair in GABA neurons in the adult hippocam-pus. Cell Cycle 2010;9:1-3.9. KATSEL P, DAVIS KL, LI C, TAN W, Greenstein E, Kleiner Hoﬀ man LB, Haroutuian V. Abnormal indices of cell cycle activity in schizphrenia in association with oligo-dendrocytes. Neuropsychopharmacology 2008; 33: 2993-3009.10. HAYES TE, VALTZ NL, MCKAY RD. Downregulation of CDC2 upon terminal diﬀ erentiation  of neurons. New Biol. 1991; 3:259-269.11. MAĆKOWIAK M, KOLASIEWICZ W, MARKOWICZKULA K, WEDZONY K. Purvalanol A, inhibitor of cyclin-dependent kinases attenuates proliferation of cells in the dentate gyrus of the adult rat hippocampus Pharmacol Rep. 2005; 57:845-849.12. MAO Y, GE X, FRANK CL, MADISON JM, KOEHLER AN, DOUD MK, TASSA C, BERRY EM, SODA T, SINGH KK, BIECHELE T, PETRYSHEN TL, MOON RT, HAGGARTY SJ, TSAI LH. Disrupted in schizophre-nia 1 regulates neuronal progenitor proliferation via modula-tion of GSK3beta/beta-catenin signaling. Cell. 20;136:1017-1031.13. BATH KG, LEE FS. Neurotrophic factor control of adult SVZ neurogenesis. Dev Neurobiol. 2010 Feb 22. [Epub ahead of print].14. REIF A, FRITZEN S, FINGER M, STROBEL A, LAUER M, SCHMITT A, LESCH KP. Neural stem cell prolif-eration is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006; 11:514-22.15. KEILHOFF G, BERNSTEIN HG, BECKER A, GRECKSCH G, WOLF G. Increased neurogenesis in a rat ketamine model of schizophrenia. Biol Psychiatry. 2004; 56: 317-322.16. KEILHOFF G, GRECKSCH G, BERNSTEIN HG, ROSKODEN T, BECKER A. Risperidone and haloperidol promote survival of stem cells in the rat hippocampus. Eur Arch Psychiatr Clin Neurosci 2010; 260:151-162. 17. BERNSTEIN HG, STEINER J, BOGERTS B. Glial cells in schizophrenia: pathophysiological signiﬁ cance and possi-ble consequences for therapy. Expert Rev Neurother. 2009; 9:1059-1071.18. MERKWIRTH C, DARGAZANLI S, TATSUTA T, GEIMER S, LÖWER B, WUNDERLICH FT, VON KLEISTRETZOW JC, WESTERMANN B, LANGER T. Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mito-cheondria. Genes Dev. 2008;22, 476-488.19. SMALLA KH, MIKHAYLOVA M, SAHIN J, BERNSTEIN HG, BOGERTS B, SCHMITT A, VAN DER SCHORS R, SMIT AB, LI KW, GUNDELFINGER ED, KREUTZ MR. A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia. Mol Psychiatry. 2008; 13:878-896. 20. WANG L, LOCKSTONE HE, GUEST PC, LEVIN Y, PALOTÁS A, PIETSCH S, SCHWARZ E, RAHMOUNE R, HARRIS LW, MA D, BAHN S. Expression proﬁ ling of ﬁ broblasts identiﬁ es cell cycle abnormalities in schizophrenia. J Proteome Res. 2010; 9:521-527.

Cell Cycle Disturbances in Schizophrenia: The Journey So Far

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