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Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

Molecular Psychiatry volume 13, pages 173–186 (2008)Cite this article

Abstract

A strong candidate gene for schizophrenia and major mental disorders, disrupted-in-schizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.

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References

  1. Carpenter Jr WT, Buchanan RW . Schizophrenia. N Engl J Med 1994; 330: 681–690.

    Article  PubMed  Google Scholar 

  2. Tamminga CA, Holcomb HH . Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 2005; 10: 27–39.

    Article  CAS  PubMed  Google Scholar 

  3. Tamminga CA . Gender and schizophrenia. J Clin Psychiatry 1997; 58 (Suppl 15): 33–37.

    PubMed  Google Scholar 

  4. Leung A, Chue P . Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl 2000; 401: 3–38.

    Article  CAS  PubMed  Google Scholar 

  5. Millar JK, James R, Brandon NJ, Thomson PA . DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness. Ann Med 2004; 36: 367–378.

    Article  CAS  PubMed  Google Scholar 

  6. Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68; image 5.

    Article  CAS  PubMed  Google Scholar 

  7. Millar JK, Christie S, Anderson S, Lawson D, Hsiao-Wei Loh D, Devon RS et al. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 2001; 6: 173–178.

    Article  CAS  PubMed  Google Scholar 

  8. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13–16.

    Article  CAS  PubMed  Google Scholar 

  9. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.

    CAS  PubMed  Google Scholar 

  10. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 2005; 62: 1205–1213.

    Article  CAS  PubMed  Google Scholar 

  11. Chen QY, Chen Q, Feng GY, Lindpaintner K, Wang LJ, Chen ZX et al. Case-control association study of disrupted-in-schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population. J Psychiatr Res 2007; 41: 428–434.

    Article  PubMed  Google Scholar 

  12. Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA et al. Identification of polymorphisms within disrupted in schizophrenia 1 and disrupted in schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11: 71–78.

    Article  CAS  PubMed  Google Scholar 

  13. Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.

    CAS  PubMed  Google Scholar 

  14. Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T et al. A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry 2005; 10: 1097–1103.

    Article  CAS  PubMed  Google Scholar 

  15. Maeda K, Nwulia E, Chang J, Balkissoon R, Ishizuka K, Chen H et al. Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder. Biol Psychiatry 2006; 60: 929–935.

    Article  PubMed  Google Scholar 

  16. Thomson PA, Wray NR, Millar JK, Evans KL, Hellard SL, Condie A et al. Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol Psychiatry 2005; 10: 657–668, 616.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang X, Tochigi M, Ohashi J, Maeda K, Kato T, Okazaki Y et al. Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population. Schizophr Res 2005; 79: 175–180.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Austin CP, Ma L, Ky B, Morris JA, Shughrue PJ . DISC1 (Disrupted in Schizophrenia-1) is expressed in limbic regions of the primate brain. Neuroreport 2003; 14: 951–954.

    Article  CAS  PubMed  Google Scholar 

  20. Ma L, Liu Y, Ky B, Shughrue PJ, Austin CP, Morris JA . Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1). Genomics 2002; 80: 662–672.

    Article  CAS  PubMed  Google Scholar 

  21. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K et al. Disrupted-in-schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 2003; 100: 289–294.

    Article  CAS  PubMed  Google Scholar 

  22. Millar JK, Christie S, Porteous DJ . Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 2003; 311: 1019–1025.

    Article  CAS  PubMed  Google Scholar 

  23. Morris JA, Kandpal G, Ma L, Austin CP . DISC1 (Disrupted-in-schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 2003; 12: 1591–1608.

    Article  CAS  PubMed  Google Scholar 

  24. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S et al. Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 2007; 12: 74–86.

    Article  CAS  PubMed  Google Scholar 

  25. Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T et al. Disrupted in schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 2003; 8: 685–694.

    Article  CAS  PubMed  Google Scholar 

  26. Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B et al. Disrupted in schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 2004; 25: 42–55.

    Article  CAS  PubMed  Google Scholar 

  27. Brandon NJ, Schurov I, Camargo LM, Handford EJ, Duran-Jimeniz B, Hunt P et al. Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. Mol Cell Neurosci 2005; 28: 613–624.

    Article  CAS  PubMed  Google Scholar 

  28. Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M et al. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet 2006; 15: 3313–3323.

    Article  CAS  PubMed  Google Scholar 

  29. Shinoda T, Taya S, Tsuboi D, Hikita T, Matsuzawa R, Kuroda S et al. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci 2007; 27: 4–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taya S, Shinoda T, Tsuboi D, Asaki J, Nagai K, Hikita T et al. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci 2007; 27: 15–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005; 310: 1187–1191.

    Article  CAS  PubMed  Google Scholar 

  32. Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y et al. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry 2007 (in press).

  33. Grabher C, von Boehmer H, Look AT . Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006; 6: 347–359.

    Article  CAS  PubMed  Google Scholar 

  34. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005; 7: 1167–1178.

    Article  PubMed  Google Scholar 

  35. Buchanan RW, Carpenter Jr WT . The neuroanatomies of schizophrenia. Schizophr Bull 1997; 23: 367–372.

    Article  CAS  PubMed  Google Scholar 

  36. Harrison PJ . The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 2004; 174: 151–162.

    Article  CAS  Google Scholar 

  37. McCullumsmith RE, Clinton SM, Meador-Woodruff JH . Schizophrenia as a disorder of neuroplasticity. Int Rev Neurobiol 2004; 59: 19–45.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT . Neurobiology of schizophrenia. Neuron 2006; 52: 139–153.

    Article  CAS  PubMed  Google Scholar 

  40. Taylor MS, Devon RS, Millar JK, Porteous DJ . Evolutionary constraints on the disrupted in schizophrenia locus. Genomics 2003; 81: 67–77.

    Article  CAS  PubMed  Google Scholar 

  41. Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER . Control of memory formation through regulated expression of a CaMKII transgene. Science 1996; 274: 1678–1683.

    Article  CAS  PubMed  Google Scholar 

  42. Murphy G, Lowing L, Heng M, Albin R, McKinney B . Decreased exploratory behavior observed in C57BL/6 CamKIIα-tTA mice persists in F1 C57BL/6:129 Sve hybrid background. Abstract, Society Neurosci, Altlanta, 2006, 668.13/JJ24.

  43. Schneider J, Schaffer G, McKinney B, Mohan S, Murphy G, Seasholtz A et al. Expression of the tetracycline transactivator gene under regulation of the CaMKII promoter causes anxiety-like phenotype in mice. Abstract, Society Neurosci, Altlanta, 2006, #488.6/PP13 (http://www.abstractsonline.com/viewer/?mkey=%7BD1974E76%2D28AF%2D4C1C%2D8AE8%2D4F73B56247A7%7D).

  44. Rios O, Villalobos J . Postnatal development of the afferent projections from the dorsomedial thalamic nucleus to the frontal cortex in mice. Brain Res Dev Brain Res 2004; 150: 47–50.

    Article  CAS  PubMed  Google Scholar 

  45. Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron 2005; 45: 279–291.

    Article  CAS  PubMed  Google Scholar 

  46. Melvin NR, Dyck RH . Developmental distribution of calretinin in mouse barrel cortex. Brain Res Dev Brain Res 2003; 143: 111–114.

    Article  CAS  PubMed  Google Scholar 

  47. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE . beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992; 12: 376–389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sholl DA . Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 1953; 87: 387–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Rodriguiz RM, Chu R, Caron MG, Wetsel WC . Aberrant responses in social interaction of dopamine transporter knockout mice. Behav Brain Res 2004; 148: 185–198.

    Article  CAS  PubMed  Google Scholar 

  50. Crawley JN . Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 2004; 10: 248–258.

    Article  PubMed  Google Scholar 

  51. Moran TH, Capone GT, Knipp S, Davisson MT, Reeves RH, Gearhart JD . The effects of piracetam on cognitive performance in a mouse model of Down's syndrome. Physiol Behav 2002; 77: 403–409.

    Article  CAS  PubMed  Google Scholar 

  52. Eastwood SL . The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame? Int Rev Neurobiol 2004; 59: 47–72.

    Article  CAS  PubMed  Google Scholar 

  53. Honer WG, Young CE . Presynaptic proteins and schizophrenia. Int Rev Neurobiol 2004; 59: 175–199.

    Article  CAS  PubMed  Google Scholar 

  54. Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.

    CAS  PubMed  Google Scholar 

  55. Porteous DJ, Millar JK . Disrupted in schizophrenia 1: building brains and memories. Trends Mol Med 2006; 12: 255–261.

    Article  CAS  PubMed  Google Scholar 

  56. Ayala R, Shu T, Tsai LH . Trekking across the brain: the journey of neuronal migration. Cell 2007; 128: 29–43.

    Article  CAS  PubMed  Google Scholar 

  57. Pletnikov M, Xu Y, Ovanesov M, Kamiya A, Sawa A, Ross C . PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation. Neurosci Res 2007; 58: 234–244.

    Article  CAS  PubMed  Google Scholar 

  58. Lipska BK, Peters T, Hyde TM, Halim N, Horowitz C, Mitkus S et al. Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Hum Mol Genet 2006; 15: 1245–1258.

    Article  CAS  PubMed  Google Scholar 

  59. Arnold SE, Talbot K, Hahn CG . Neurodevelopment, neuroplasticity, and new genes for schizophrenia. Prog Brain Res 2005; 147: 319–345.

    Article  CAS  PubMed  Google Scholar 

  60. Fatemi SH, Earle JA, Stary JM, Lee S, Sedgewick J . Altered levels of the synaptosomal associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia. Neuroreport 2001; 12: 3257–3262.

    Article  CAS  PubMed  Google Scholar 

  61. Church SM, Cotter D, Bramon E, Murray RM . Does schizophrenia result from developmental or degenerative processes? J Neural Transm Suppl 2002; 63: 129–147.

    Google Scholar 

  62. Wong AH, Van Tol HH . Schizophrenia: from phenomenology to neurobiology. Neurosci Biobehav Rev 2003; 27: 269–306.

    Article  PubMed  Google Scholar 

  63. Carlsson A, Carlsson ML . A dopaminergic deficit hypothesis of schizophrenia: the path to discovery. Dialogues Clin Neurosci 2006; 8: 137–142.

    PubMed  PubMed Central  Google Scholar 

  64. Gainetdinov RR, Mohn AR, Caron MG . Genetic animal models: focus on schizophrenia. Trends Neurosci 2001; 24: 527–533.

    Article  CAS  PubMed  Google Scholar 

  65. Brandeis R, Brandys Y, Yehuda S . The use of the Morris water maze in the study of memory and learning. Int J Neurosci 1989; 48: 29–69.

    Article  CAS  PubMed  Google Scholar 

  66. Nasser EH, Walders N, Jenkins JH . The experience of schizophrenia: what's gender got to do with it? A critical review of the current status of research on schizophrenia. Schizophr Bull 2002; 28: 351–362.

    Article  PubMed  Google Scholar 

  67. Javed MA . Gender and schizophrenia. J Pak Med Assoc 2000; 50: 63–68.

    CAS  PubMed  Google Scholar 

  68. Lindamer LA, Lohr JB, Harris MJ, Jeste DV . Gender, estrogen, and schizophrenia. Psychopharmacol Bull 1997; 33: 221–228.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Akira Sawa (Department of Psychiatry and Behavioral Sciences, Program in Molecular Psychiatry, Johns Hopkins University School of Medicine) and the members of his laboratory, Drs Atsushi Kamiya, Koko Ishizuka and Takatoshi Hikida, for their generous gift of the plasmids and helpful discussions of the initial cloning and immunoprecipitation experiments. We appreciate the support of Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. This work was supported by the grants from the Stanley Medical Research Institute (MVP), National Alliance for Research on Schizophrenia and Depression (NARSAD, Distinguished Investigator Award) (CAR), RO1EB003543 (SM) and MH077792-01A1 (MVP).

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Authors and Affiliations

  1. Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M V Pletnikov, Y Ayhan, O Nikolskaia, Y Xu, M V Ovanesov & C A Ross

  2. Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M V Pletnikov, Y Ayhan, O Nikolskaia, Y Xu, M V Ovanesov, T H Moran & C A Ross

  3. Radiology-Magnetic Resonance Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H Huang & S Mori

  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C A Ross

  5. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C A Ross

  6. Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C A Ross

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  1. M V Pletnikov
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Pletnikov, M., Ayhan, Y., Nikolskaia, O. et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry 13, 173–186 (2008). https://doi.org/10.1038/sj.mp.4002079

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