Skip to main content

Psychiatric Genetics and the Generation of Mutant Animal Models

  • Protocol
  • First Online:
Animal Models of Schizophrenia and Related Disorders

Part of the book series: Neuromethods ((NM,volume 59))

  • 774 Accesses

Abstract

Accumulating evidence indicates that the genetic architecture of psychiatric disorders does not strictly conform to the common disease/common allele hypothesis. The contribution of common genetic variants, while likely, may be fundamentally different from those of rare genetic variants. It is possible that common alleles do not increase disease risk per se but are disease modifiers sculpting the psychopathological landscape produced by rare alleles. Unlike common alleles, the statistical association of rare alleles is usually more robust and their functional effects more translatable into etiologically valid animal models. Although rare alleles may not be shared across individuals with the same diagnosis, the comparison of multiple animal models of rare risk alleles can identify common pathogenetic mechanisms. Thus, paradoxically, the cumulative evidence gathered from these animal models is currently poised to offer more insight into common psychiatric disorders than are models of common alleles.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abbott, A. (2008) Psychiatric genetics: the brains of the family, Nature 454, 154–157.

    Article  PubMed  CAS  Google Scholar 

  2. Arguello, P. A., and Gogos, J. A. (2006) Modeling madness in mice: one piece at a time, Neuron 52, 179–196.

    Article  PubMed  CAS  Google Scholar 

  3. Desbonnet, L., Waddington, J. L., and O’Tuathaigh, C. M. (2009) Mutant models for genes associated with schizophrenia, Biochem Soc Trans 37, 308–312.

    Article  PubMed  CAS  Google Scholar 

  4. Altshuler, D., Daly, M. J., and Lander, E. S. (2008) Genetic mapping in human disease, Science 322, 881–888.

    Article  PubMed  CAS  Google Scholar 

  5. Need, A. C., Ge, D., Weale, M. E., Maia, J., Feng, S., Heinzen, E. L., Shianna, K. V., Yoon, W., Kasperaviciute, D., Gennarelli, M., Strittmatter, W. J., Bonvicini, C., Rossi, G., Jayathilake, K., Cola, P. A., McEvoy, J. P., Keefe, R. S., Fisher, E. M., St Jean, P. L., Giegling, I., Hartmann, A. M., Moller, H. J., Ruppert, A., Fraser, G., Crombie, C., Middleton, L. T., St Clair, D., Roses, A. D., Muglia, P., Francks, C., Rujescu, D., Meltzer, H. Y., and Goldstein, D. B. (2009) A genome-wide investigation of SNPs and CNVs in schizophrenia, PLoS Genet 5, e1000373.

    Article  PubMed  Google Scholar 

  6. Sanders, A. R., Duan, J., Levinson, D. F., Shi, J., He, D., Hou, C., Burrell, G. J., Rice, J. P., Nertney, D. A., Olincy, A., Rozic, P., Vinogradov, S., Buccola, N. G., Mowry, B. J., Freedman, R., Amin, F., Black, D. W., Silverman, J. M., Byerley, W. F., Crowe, R. R., Cloninger, C. R., Martinez, M., and Gejman, P. V. (2008) No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics, Am J Psychiatry 165, 497–506.

    Article  PubMed  Google Scholar 

  7. Ferreira, M. A., O’Donovan, M. C., Meng, Y. A., Jones, I. R., Ruderfer, D. M., Jones, L., Fan, J., Kirov, G., Perlis, R. H., Green, E. K., Smoller, J. W., Grozeva, D., Stone, J., Nikolov, I., Chambert, K., Hamshere, M. L., Nimgaonkar, V. L., Moskvina, V., Thase, M. E., Caesar, S., Sachs, G. S., Franklin, J., Gordon-Smith, K., Ardlie, K. G., Gabriel, S. B., Fraser, C., Blumenstiel, B., Defelice, M., Breen, G., Gill, M., Morris, D. W., Elkin, A., Muir, W. J., McGhee, K. A., Williamson, R., MacIntyre, D. J., MacLean, A. W., St, C. D., Robinson, M., Van Beck, M., Pereira, A. C., Kandaswamy, R., McQuillin, A., Collier, D. A., Bass, N. J., Young, A. H., Lawrence, J., Ferrier, I. N., Anjorin, A., Farmer, A., Curtis, D., Scolnick, E. M., McGuffin, P., Daly, M. J., Corvin, A. P., Holmans, P. A., Blackwood, D. H., Gurling, H. M., Owen, M. J., Purcell, S. M., Sklar, P., and Craddock, N. (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder, Nat Genet 40, 1056–1058.

    Article  PubMed  CAS  Google Scholar 

  8. O’Donovan, M. C., Craddock, N., Norton, N., Williams, H., Peirce, T., Moskvina, V., Nikolov, I., Hamshere, M., Carroll, L., Georgieva, L., Dwyer, S., Holmans, P., Marchini, J. L., Spencer, C. C., Howie, B., Leung, H. T., Hartmann, A. M., Moller, H. J., Morris, D. W., Shi, Y., Feng, G., Hoffmann, P., Propping, P., Vasilescu, C., Maier, W., Rietschel, M., Zammit, S., Schumacher, J., Quinn, E. M., Schulze, T. G., Williams, N. M., Giegling, I., Iwata, N., Ikeda, M., Darvasi, A., Shifman, S., He, L., Duan, J., Sanders, A. R., Levinson, D. F., Gejman, P. V., Cichon, S., Nothen, M. M., Gill, M., Corvin, A., Rujescu, D., Kirov, G., Owen, M. J., Buccola, N. G., Mowry, B. J., Freedman, R., Amin, F., Black, D. W., Silverman, J. M., Byerley, W. F., and Cloninger, C. R. (2008) Identification of loci associated with schizophrenia by genome-wide association and follow-up, Nat Genet 40, 1053–1055.

    Article  PubMed  Google Scholar 

  9. Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S., Salyakina, D., Imielinski, M., Bradfield, J. P., Sleiman, P. M., Kim, C. E., Hou, C., Frackelton, E., Chiavacci, R., Takahashi, N., Sakurai, T., Rappaport, E., Lajonchere, C. M., Munson, J., Estes, A., Korvatska, O., Piven, J., Sonnenblick, L. I., Alvarez Retuerto, A. I., Herman, E. I., Dong, H., Hutman, T., Sigman, M., Ozonoff, S., Klin, A., Owley, T., Sweeney, J. A., Brune, C. W., Cantor, R. M., Bernier, R., Gilbert, J. R., Cuccaro, M. L., McMahon, W. M., Miller, J., State, M. W., Wassink, T. H., Coon, H., Levy, S. E., Schultz, R. T., Nurnberger, J. I., Haines, J. L., Sutcliffe, J. S., Cook, E. H., Minshew, N. J., Buxbaum, J. D., Dawson, G., Grant, S. F., Geschwind, D. H., Pericak-Vance, M. A., Schellenberg, G. D., and Hakonarson, H. (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders, Nature 459(7246), 528–533.

    Google Scholar 

  10. Ioannidis, J. P., Thomas, G., and Daly, M. J. (2009) Validating, augmenting and refining genome-wide association signals, Nat Rev Genet 10, 318–329.

    Article  PubMed  CAS  Google Scholar 

  11. Frazer, K. A., Murray, S. S., Schork, N. J., and Topol, E. J. (2009) Human genetic variation and its contribution to complex traits, Nat Rev Genet 10, 241–251.

    Article  PubMed  CAS  Google Scholar 

  12. Bodmer, W., and Bonilla, C. (2008) Common and rare variants in multifactorial susceptibility to common diseases, Nat Genet 40, 695–701.

    Article  PubMed  CAS  Google Scholar 

  13. Xu, B., Roos, J. L., Levy, S., van Rensburg, E. J., Gogos, J. A., and Karayiorgou, M. (2008) Strong association of de novo copy number mutations with sporadic schizophrenia, Nat Genet 40, 880–885.

    Article  PubMed  CAS  Google Scholar 

  14. ISC. (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia, Nature 455, 237–241.

    Article  Google Scholar 

  15. Karayiorgou, M., Morris, M. A., Morrow, B., Shprintzen, R. J., Goldberg, R., Borrow, J., Gos, A., Nestadt, G., Wolyniec, P. S., Lasseter, V. K., et al. (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11, Proc Natl Acad Sci USA 92, 7612–7616.

    Article  PubMed  CAS  Google Scholar 

  16. Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O. P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J. E., Hansen, T., Jakobsen, K. D., Muglia, P., Francks, C., Matthews, P. M., Gylfason, A., Halldorsson, B. V., Gudbjartsson, D., Thorgeirsson, T. E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B. B., Giegling, I., Moller, H. J., Hartmann, A., Shianna, K. V., Ge, D., Need, A. C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T. W., Wang, A. G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L. A., Franke, B., Sabatti, C., Freimer, N. B., Gulcher, J. R., Thorsteinsdottir, U., Kong, A., Andreassen, O. A., Ophoff, R. A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D. B., Nothen, M. M., Peltonen, L., Collier, D. A., St Clair, D., and Stefansson, K. (2008) Large recurrent microdeletions associated with schizophrenia, Nature 455, 232–236.

    Article  PubMed  CAS  Google Scholar 

  17. St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., Gosden, C., and Evans, H. J. (1990) Association within a family of a balanced autosomal translocation with major mental illness, Lancet 336, 13–16.

    Article  PubMed  CAS  Google Scholar 

  18. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y. H., Hicks, J., Spence, S. J., Lee, A. T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P. K., Bregman, J., Sutcliffe, J. S., Jobanputra, V., Chung, W., Warburton, D., King, M. C., Skuse, D., Geschwind, D. H., Gilliam, T. C., Ye, K., and Wigler, M. (2007) Strong association of de novo copy number mutations with autism, Science 316, 445–449.

    Article  PubMed  CAS  Google Scholar 

  19. Goldstein, D. B. (2009) Common genetic variation and human traits, N Engl J Med 360, 1696–1698.

    Article  PubMed  CAS  Google Scholar 

  20. Fan, J. B., Zhang, C. S., Gu, N. F., Li, X. W., Sun, W. W., Wang, H. Y., Feng, G. Y., St Clair, D., and He, L. (2005) Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis, Biol Psychiatry 57, 139–144.

    Article  PubMed  CAS  Google Scholar 

  21. Kanazawa, T., Glatt, S. J., Kia-Keating, B., Yoneda, H., and Tsuang, M. T. (2007) Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder, Psychiatr Genet 17, 165–170.

    Article  PubMed  Google Scholar 

  22. Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T. T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V. G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R. P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M. L., Gurney, M. E., Kong, A., Gulcher, J. R., Petursson, H., and Stefansson, K. (2002) Neuregulin 1 and susceptibility to schizophrenia, Am J Hum Genet 71, 877–892.

    Article  PubMed  Google Scholar 

  23. Law, A. J., Kleinman, J. E., Weinberger, D. R., Weickert, C. S. (2007) Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia, Hum Mol Genet 16(2), 129–141.

    Article  PubMed  CAS  Google Scholar 

  24. Mei, L., and Xiong, W. C. (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia, Nat Rev Neurosci 9, 437–452.

    Article  PubMed  CAS  Google Scholar 

  25. Gerlai, R., Pisacane, P., and Erickson, S. (2000) Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks, Behav Brain Res 109, 219–227.

    Article  PubMed  CAS  Google Scholar 

  26. O’Tuathaigh, C. M., Babovic, D., O’Sullivan, G. J., Clifford, J. J., Tighe, O., Croke, D. T., Harvey, R., and Waddington, J. L. (2007) Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1, Neuroscience 147, 18–27.

    Article  PubMed  Google Scholar 

  27. O’Tuathaigh, C. M., O’Connor, A. M., O’Sullivan, G. J., Lai, D., Harvey, R., Croke, D. T., and Waddington, J. L. (2008) Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous ‘knockout’ of the schizophrenia risk gene neuregulin-1, Prog Neuropsychopharmacol Biol Psychiatry 32, 462–466.

    Article  PubMed  Google Scholar 

  28. Rimer, M., Barrett, D. W., Maldonado, M. A., Vock, V. M., and Gonzalez-Lima, F. (2005) Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition, Neuroreport 16, 271–275.

    Article  PubMed  CAS  Google Scholar 

  29. Roy, K., Murtie, J. C., El-Khodor, B. F., Edgar, N., Sardi, S. P., Hooks, B. M., Benoit-Marand, M., Chen, C., Moore, H., O’Donnell, P., Brunner, D., and Corfas, G. (2007) Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders, Proc Natl Acad Sci USA 104, 8131–8136.

    Article  PubMed  CAS  Google Scholar 

  30. Barros, C. S., Calabrese, B., Chamero, P., Roberts, A. J., Korzus, E., Lloyd, K., Stowers, L., Mayford, M., Halpain, S., and Muller, U. (2009) Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system, Proc Natl Acad Sci USA 106, 4507–4512.

    Article  PubMed  CAS  Google Scholar 

  31. Savonenko, A. V., Melnikova, T., Laird, F. M., Stewart, K. A., Price, D. L., and Wong, P. C. (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice, Proc Natl Acad Sci USA 105, 5585–5590.

    Article  PubMed  CAS  Google Scholar 

  32. Ohno, M., Sametsky, E. A., Younkin, L. H., Oakley, H., Younkin, S. G., Citron, M., Vassar, R., and Disterhoft, J. F. (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease, Neuron 41, 27–33.

    Article  PubMed  CAS  Google Scholar 

  33. Li, W., Zhang, Q., Oiso, N., Novak, E. K., Gautam, R., O’Brien, E. P., Tinsley, C. L., Blake, D. J., Spritz, R. A., Copeland, N. G., Jenkins, N. A., Amato, D., Roe, B. A., Starcevic, M., Dell’Angelica, E. C., Elliott, R. W., Mishra, V., Kingsmore, S. F., Paylor, R. E., and Swank, R. T. (2003) Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1), Nat Genet 35, 84–89.

    Article  PubMed  CAS  Google Scholar 

  34. Takao, K., Toyama, K., Nakanishi, K., Hattori, S., Takamura, H., Takeda, M., Miyakawa, T., and Hashimoto, R. (2008) Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia, Mol Brain 1, 11.

    Article  PubMed  Google Scholar 

  35. Bhardwaj, S. K., Baharnoori, M., Sharif-Askari, B., Kamath, A., Williams, S., and Srivastava, L. K. (2009) Behavioral characterization of dysbindin-1 deficient sandy mice, Behav Brain Res 197, 435–441.

    Article  PubMed  CAS  Google Scholar 

  36. Feng, Y. Q., Zhou, Z. Y., He, X., Wang, H., Guo, X. L., Hao, C. J., Guo, Y., Zhen, X. C., and Li, W. (2008) Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia, Schizophr Res 106, 218–228.

    Article  PubMed  Google Scholar 

  37. Cox, M. M., Tucker, A. M., Tang, J., Talbot, K., Richer, D. C., Yeh, L., and Arnold, S. E. (2009) Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6 J genetic background, Genes Brain Behav 8(4), 390–397.

    Google Scholar 

  38. Chen, X. W., Feng, Y. Q., Hao, C. J., Guo, X. L., He, X., Zhou, Z. Y., Guo, N., Huang, H. P., Xiong, W., Zheng, H., Zuo, P. L., Zhang, C. X., Li, W., and Zhou, Z. (2008) DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release, J Cell Biol 181, 791–801.

    Article  PubMed  CAS  Google Scholar 

  39. Murotani, T., Ishizuka, T., Hattori, S., Hashimoto, R., Matsuzaki, S., and Yamatodani, A. (2007) High dopamine turnover in the brains of Sandy mice, Neurosci Lett 421, 47–51.

    Article  PubMed  CAS  Google Scholar 

  40. Weickert, C. S., Straub, R. E., McClintock, B. W., Matsumoto, M., Hashimoto, R., Hyde, T. M., Herman, M. M., Weinberger, D. R., and Kleinman, J. E. (2004) Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain, Arch Gen Psychiatry 61, 544–555.

    Article  PubMed  CAS  Google Scholar 

  41. Gerber, D. J., Hall, D., Miyakawa, T., Demars, S., Gogos, J. A., Karayiorgou, M., and Tonegawa, S. (2003) Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit, Proc Natl Acad Sci USA 100, 8993–8998.

    Article  PubMed  CAS  Google Scholar 

  42. Miyakawa, T., Leiter, L. M., Gerber, D. J., Gainetdinov, R. R., Sotnikova, T. D., Zeng, H., Caron, M. G., and Tonegawa, S. (2003) Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia, Proc Natl Acad Sci USA 100, 8987–8992.

    Article  PubMed  CAS  Google Scholar 

  43. Zeng, H., Chattarji, S., Barbarosie, M., Rondi-Reig, L., Philpot, B. D., Miyakawa, T., Bear, M. F., and Tonegawa, S. (2001) Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory, Cell 107, 617–629.

    Article  PubMed  CAS  Google Scholar 

  44. Greengard, P., Allen, P. B., and Nairn, A. C. (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade, Neuron 23, 435–447.

    Article  PubMed  CAS  Google Scholar 

  45. Cousin, M. A., and Robinson, P. J. (2001) The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis, Trends Neurosci 24, 659–665.

    Article  PubMed  CAS  Google Scholar 

  46. Emamian, E. S., Hall, D., Birnbaum, M. J., Karayiorgou, M., and Gogos, J. A. (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia, Nat Genet 36, 131–137.

    Article  PubMed  CAS  Google Scholar 

  47. Beaulieu, J. M., Sotnikova, T. D., Marion, S., Lefkowitz, R. J., Gainetdinov, R. R., and Caron, M. G. (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior, Cell 122, 261–273.

    Article  PubMed  CAS  Google Scholar 

  48. Arguello, P. A., and Gogos, J. A. (2008) A signaling pathway AKTing up in schizophrenia, J Clin Invest 118, 2018–2021.

    PubMed  CAS  Google Scholar 

  49. Chubb, J. E., Bradshaw, N. J., Soares, D. C., Porteous, D. J., and Millar, J. K. (2008) The DISC locus in psychiatric illness, Mol Psychiatry 13, 36–64.

    Article  PubMed  CAS  Google Scholar 

  50. Schumacher, J., Laje, G., Abou Jamra, R., Becker, T., Muhleisen, T. W., Vasilescu, C., Mattheisen, M., Herms, S., Hoffmann, P., Hillmer, A. M., Georgi, A., Herold, C., Schulze, T. G., Propping, P., Rietschel, M., McMahon, F. J., Nothen, M. M., and Cichon, S. (2009) The DISC locus and schizophrenia – Evidence from an association study in a central European sample and from a meta-analysis across different European populations, Hum Mol Genet 18(14), 2719–2727.

    Google Scholar 

  51. Duan, X., Chang, J. H., Ge, S., Faulkner, R. L., Kim, J. Y., Kitabatake, Y., Liu, X. B., Yang, C. H., Jordan, J. D., Ma, D. K., Liu, C. Y., Ganesan, S., Cheng, H. J., Ming, G. L., Lu, B., and Song, H. (2007) Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain, Cell 130, 1146–1158.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  53. Mao, Y., Ge, X., Frank, C. L., Madison, J. M., Koehler, A. N., Doud, M. K., Tassa, C., Berry, E. M., Soda, T., Singh, K. K., Biechele, T., Petryshen, T. L., Moon, R. T., Haggarty, S. J., and Tsai, L. H. (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling, Cell 136, 1017–1031.

    Article  PubMed  CAS  Google Scholar 

  54. Kvajo, M., McKellar, H., Arguello, P. A., Drew, L. J., Moore, H., MacDermott, A. B., Karayiorgou, M., and Gogos, J. A. (2008) A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition, Proc Natl Acad Sci USA 105, 7076–7081.

    Article  PubMed  CAS  Google Scholar 

  55. Koike, H., Arguello, P. A., Kvajo, M., Karayiorgou, M., and Gogos, J. A. (2006) Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice, Proc Natl Acad Sci USA 103, 3693–3697.

    Article  PubMed  CAS  Google Scholar 

  56. Hikida, T., Jaaro-Peled, H., Seshadri, S., Oishi, K., Hookway, C., Kong, S., Wu, D., Xue, R., Andrade, M., Tankou, S., Mori, S., Gallagher, M., Ishizuka, K., Pletnikov, M., Kida, S., and Sawa, A. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans, Proc Natl Acad Sci USA 104, 14501–14506.

    Article  PubMed  CAS  Google Scholar 

  57. Pletnikov, M. V., Ayhan, Y., Nikolskaia, O., Xu, Y., Ovanesov, M. V., Huang, H., Mori, S., Moran, T. H., and Ross, C. A. (2008) Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia, Mol Psychiatry 13, 173–186, 115.

    Article  PubMed  CAS  Google Scholar 

  58. Li, W., Zhou, Y., Jentsch, J. D., Brown, R. A., Tian, X., Ehninger, D., Hennah, W., Peltonen, L., Lonnqvist, J., Huttunen, M. O., Kaprio, J., Trachtenberg, J. T., Silva, A. J., and Cannon, T. D. (2007) Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice, Proc Natl Acad Sci USA 104, 18280–18285.

    Article  PubMed  CAS  Google Scholar 

  59. Shen, S., Lang, B., Nakamoto, C., Zhang, F., Pu, J., Kuan, S. L., Chatzi, C., He, S., Mackie, I., Brandon, N. J., Marquis, K. L., Day, M., Hurko, O., McCaig, C. D., Riedel, G., and St Clair, D. (2008) Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1, J Neurosci 28, 10893–10904.

    Article  PubMed  CAS  Google Scholar 

  60. Kimber, W. L., Hsieh, P., Hirotsune, S., Yuva-Paylor, L., Sutherland, H. F., Chen, A., Ruiz-Lozano, P., Hoogstraten-Miller, S. L., Chien, K. R., Paylor, R., Scambler, P. J., and Wynshaw-Boris, A. (1999) Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse, Hum Mol Genet 8, 2229–2237.

    Article  PubMed  CAS  Google Scholar 

  61. Paylor, R., McIlwain, K. L., McAninch, R., Nellis, A., Yuva-Paylor, L. A., Baldini, A., and Lindsay, E. A. (2001) Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments, Hum Mol Genet 10, 2645–2650.

    Article  PubMed  CAS  Google Scholar 

  62. Long, J. M., LaPorte, P., Merscher, S., Funke, B., Saint-Jore, B., Puech, A., Kucherlapati, R., Morrow, B. E., Skoultchi, A. I., and Wynshaw-Boris, A. (2006) Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome, Neurogenetics 7, 247–257.

    Article  PubMed  Google Scholar 

  63. Stark, K. L., Xu, B., Bagchi, A., Lai, W. S., Liu, H., Hsu, R., Wan, X., Pavlidis, P., Mills, A. A., Karayiorgou, M., and Gogos, J. A. (2008) Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model, Nat Genet 40, 751–760.

    Article  PubMed  CAS  Google Scholar 

  64. Gogos, J. A., Santha, M., Takacs, Z., Beck, K. D., Luine, V., Lucas, L. R., Nadler, J. V., and Karayiorgou, M. (1999) The gene encoding proline dehydrogenase modulates sensorimotor gating in mice, Nat Genet 21, 434–439.

    Article  PubMed  CAS  Google Scholar 

  65. Paterlini, M., Zakharenko, S. S., Lai, W. S., Qin, J., Zhang, H., Mukai, J., Westphal, K. G., Olivier, B., Sulzer, D., Pavlidis, P., Siegelbaum, S. A., Karayiorgou, M., and Gogos, J. A. (2005) Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice, Nat Neurosci 8, 1586–1594.

    Article  PubMed  CAS  Google Scholar 

  66. Raux, G., Bumsel, E., Hecketsweiler, B., van Amelsvoort, T., Zinkstok, J., Manouvrier-Hanu, S., Fantini, C., Breviere, G. M., Di Rosa, G., Pustorino, G., Vogels, A., Swillen, A., Legallic, S., Bou, J., Opolczynski, G., Drouin-Garraud, V., Lemarchand, M., Philip, N., Gerard-Desplanches, A., Carlier, M., Philippe, A., Nolen, M. C., Heron, D., Sarda, P., Lacombe, D., Coizet, C., Alembik, Y., Layet, V., Afenjar, A., Hannequin, D., Demily, C., Petit, M., Thibaut, F., Frebourg, T., and Campion, D. (2007) Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome, Hum Mol Genet 16, 83–91.

    Article  PubMed  CAS  Google Scholar 

  67. Vorstman, J. A., Turetsky, B. I., Sijmens-Morcus, M. E., de Sain, M. G., Dorland, B., Sprong, M., Rappaport, E. F., Beemer, F. A., Emanuel, B. S., Kahn, R. S., van Engeland, H., and Kemner, C. (2009) Proline affects brain function in 22q11DS children with the low activity COMT 158 allele, Neuropsychopharmacology 34, 739–746.

    Article  PubMed  CAS  Google Scholar 

  68. Mukai, J., Dhilla, A., Drew, L. J., Stark, K. L., Cao, L., MacDermott, A. B., Karayiorgou, M., and Gogos, J. A. (2008) Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion, Nat Neurosci 11, 1302–1310.

    Article  PubMed  CAS  Google Scholar 

  69. Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C. H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O’Donovan, M. C., Owen, M. J., Scambler, P. J., and Lindsay, E. (2006) Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome, Proc Natl Acad Sci USA 103, 7729–7734.

    Article  PubMed  CAS  Google Scholar 

  70. Mukai, J., Liu, H., Burt, R. A., Swor, D. E., Lai, W. S., Karayiorgou, M., and Gogos, J. A. (2004) Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia, Nat Genet 36, 725–731.

    Article  PubMed  CAS  Google Scholar 

  71. Gogos, J. A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., and Karayiorgou, M. (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior, Proc Natl Acad Sci USA 95, 9991–9996.

    Article  PubMed  CAS  Google Scholar 

  72. Hsu, R., Woodroffe, A., Lai, W. S., Cook, M. N., Mukai, J., Dunning, J. P., Swanson, D. J., Roos, J. L., Abecasis, G. R., Karayiorgou, M., and Gogos, J. A. (2007) Nogo receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches, PLoS One 2, e1234.

    Article  PubMed  Google Scholar 

  73. Insel, T. R. (2007) From animal models to model animals, Biol Psychiatry 62, 1337–1339.

    Article  PubMed  Google Scholar 

  74. Todd, J. A. (2006) Statistical false positive or true disease pathway? Nat Genet 38, 731–733.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratory is supported by grants from NIMH, NARSAD, and the Simons Foundation. We thank M. Karayiorgou, B. Levy, and L. Drew for critical readings of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph A. Gogos .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Arguello, P.A., Gogos, J.A. (2011). Psychiatric Genetics and the Generation of Mutant Animal Models. In: O'Donnell, P. (eds) Animal Models of Schizophrenia and Related Disorders. Neuromethods, vol 59. Humana Press. https://doi.org/10.1007/978-1-61779-157-4_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-157-4_8

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-156-7

  • Online ISBN: 978-1-61779-157-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics