Skip to main content

Genetic Mouse Models of Psychiatric Disorders

Advantages, Limitations, and Challenges

  • Chapter
Transgenic and Knockout Models of Neuropsychiatric Disorders

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

  • 697 Accesses

Abstract

The mental well-being of humans depends on the discovery of the causes of mental illnesses and the use of this knowledge to direct the generation of new treatments and the development of preventive measures. In this context, defining how we can exploit the power of animal models in investigative strategies designed to understand and manipulate candidate causal factors remains a critical challenge. The fact that mental illnesses are uniquely human disorders does not negate the feasibility of developing and using relevant animal models, but only defines the challenge and sets the limitations of an animal model. Because the field is still in its infancy, addressing the roles and targets of animal models of mental illnesses effectively and responsibly will require additional empirical data, as well as critical thinking from scientists, journal editors, and funding agencies. In this chapter, we discuss some general guidelines for the development of genetic mouse models of psychiatric disorders and offer a theoretical framework for the interpretation of their analysis. At the end, we discuss some results and practical issues emerging from our ongoing work on a genetic mouse model of schizophrenia.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant⋯or not? Hum Mol Genet 2002; 11: 2417–2423.

    Article  PubMed  CAS  Google Scholar 

  2. Carroll SB. Genetics and the making of Homo sapiens. Nature 2003;422:849–857.

    Article  PubMed  CAS  Google Scholar 

  3. Austin CP, Battey JF, Bradley A, et al. The knockout mouse project. Nat Genet 2004;36:921–924.

    Article  PubMed  CAS  Google Scholar 

  4. Auwerx J, Avner P, Baldock R, et al. The European dimension for the mouse genome mutagenesis program. Nat Genet 2004;36:925–927.

    Article  PubMed  CAS  Google Scholar 

  5. Lewandoski M. Mouse genomic technologies: conditional control of gene expression in the mouse. Nat Rev Genet 2001;2:743–755.

    Article  PubMed  CAS  Google Scholar 

  6. Miyakawa T, Leiter LM, Gerber DJ, et al. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci USA 2003; 100:8987–8992.

    Article  PubMed  CAS  Google Scholar 

  7. Gerlai R. Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci 1996;19:177–181. Erratum in: Trends Neurosci 1996;19:271.

    Article  PubMed  CAS  Google Scholar 

  8. Crabbe JC, Wahlsten D, Dudek BC. Genetics of mouse behavior: interactions with laboratory environment. Science 1999;284:1670–1672.

    Article  PubMed  CAS  Google Scholar 

  9. Cabib S, Orsini C, Le Moal M, Piazza PV. Abolition and reversal of strain differences in behavioral responses to drugs of abuse after a brief experience. Science 2000;289:463–465.

    Article  PubMed  CAS  Google Scholar 

  10. Mohn AR, Gainetdinov RR, Caron MG, Koller B.H. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999;98:427–436.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Mukai J, Liu H, Burt RA, et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet 2004;36:725–731.

    Article  PubMed  CAS  Google Scholar 

  13. Sklar P, Gabriel SB, McInnis MG, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry 2002;7:579–593.

    Article  PubMed  CAS  Google Scholar 

  14. Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112: 257–269.

    Article  PubMed  CAS  Google Scholar 

  15. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet 2003;73:370–376.

    Article  PubMed  CAS  Google Scholar 

  16. Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH Jr. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2004;161:1698–1700.

    Article  PubMed  Google Scholar 

  17. Rebbeck TR, Spitz M, Wu X. Assessing the function of genetic variants in candidate gene association studies. Nat Rev Genet 2004;5:589–597.

    Article  PubMed  CAS  Google Scholar 

  18. Braff DL. Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 1993;19:233–259.

    PubMed  CAS  Google Scholar 

  19. Perry W, Braff DL. Information-processing deficits and thought disorder in schizophrenia. Am J Psychiat 1994;151:363–367.

    PubMed  CAS  Google Scholar 

  20. Cannon TD, Zorrilla LE, Shtasel D, et al. Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers. Arch Gen Psychiat 1994;51:651–661.

    PubMed  CAS  Google Scholar 

  21. Cannon TD, Huttumen MO, Lonnqvist J, et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 2000;67:369–382.

    Article  PubMed  CAS  Google Scholar 

  22. Goldman-Rakic PS. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiat 1999;46:650–661.

    Article  PubMed  CAS  Google Scholar 

  23. Elvevag B, Goldberg TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 2000;14:1–21.

    PubMed  CAS  Google Scholar 

  24. Martins Serra A, Jones SH, Toone B, Gray JA. Impaired associative learning in chronic schizophrenics and their first-degree relatives: a study of latent inhibition and the Kamin blocking effect. Schizophr Res 2001;48:273–289.

    Article  PubMed  CAS  Google Scholar 

  25. Freimer N, Sabatti C. The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology. Nat Genet 2004;36:1045–1051.

    Article  PubMed  CAS  Google Scholar 

  26. Gerber DJ, Hall D, Miyakawa T, et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA 2003;100:8993–8998.

    Article  PubMed  CAS  Google Scholar 

  27. Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle. Cambridge, UK Cambridge University Press, 1982.

    Google Scholar 

  28. Kety SS, Wender PH, Jacobsen B, et al. Mental illness in the biological and adoptive relatives of schizophrenia adoptees. Replication of the Copenhagen study in the rest of Denmark. Arch Gen Psychiat 1994;51:442–455.

    PubMed  CAS  Google Scholar 

  29. Karayiorgou M, Gogos JA. A turning point in schizophrenia genetics. Neuron 1997;19:967–979.

    Article  PubMed  CAS  Google Scholar 

  30. Blouin JL, Dombroski BA, Nath SK, et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998;20:70–73.

    Article  PubMed  CAS  Google Scholar 

  31. Shaw SH, Kelly M, Smith AB, et al. A genome-wide search for schizophrenia susceptibility genes. Am J Med Genet 1998;81:364–376.

    Article  PubMed  CAS  Google Scholar 

  32. Williams NM, Norton N, Williams H, et al. A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 2003;73:1355–1367.

    Article  PubMed  CAS  Google Scholar 

  33. Pulver AE, Nestadt G, Goldberg R, et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 1994;182:476–478.

    PubMed  CAS  Google Scholar 

  34. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiat 1999;56:940–945.

    Article  PubMed  CAS  Google Scholar 

  35. Karayiorgou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 1995;92:7612–7616.

    Article  PubMed  CAS  Google Scholar 

  36. Usiskin SI, Nicolson R, Krasnewich DM, et al. Velocardiofacial syndrome in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiat 1999;38:1536–1543.

    Article  CAS  Google Scholar 

  37. Wiehahn GJ, Bosch GP, du Preez RR, Pretorius HW, Karayiorgou M, Roos JL. Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients. Am J Med Genet 2004;129B:20–22.

    Article  CAS  PubMed  Google Scholar 

  38. Chow EWC, Mikulis DJ, Zipursky RB, Scutt LE, Weksberg R, Bassett AS. Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia. Biol Psychiat 1999;46: 1436–1442.

    Article  PubMed  CAS  Google Scholar 

  39. Chow EWC, Zipursky RB, Mikulis DJ, Basset AS. Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome. Biol Psychiat 2002;51:208–215.

    Article  PubMed  Google Scholar 

  40. Edelmann L, Pandita RK, Morrow BE. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am J Hum Genet 1999;64:1076–1086.

    Article  PubMed  CAS  Google Scholar 

  41. Shaikh TH, Kurahashi H, Saitta SC, et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 2000;9:489-501. 42 Puech A, Saint-Jore B, Funke B, et al. Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc Natl Acad Sci USA 1997;94:14,608–14,613.

    Article  Google Scholar 

  42. Paylor R, McIlwain KL, McAninch R, et al. Mice deleted for the DGS/VCFS syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum Mol Genet 2001;10:2645–2650.

    Article  PubMed  CAS  Google Scholar 

  43. Mills AA, Bradley A. From mouse to man: generating megabase chromosome rearrangements. Trends Genet 2001;17:331–339.

    Article  PubMed  CAS  Google Scholar 

  44. Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharm 2001;156:234–258.

    Article  CAS  Google Scholar 

  45. Paylor R, Crawley JN. Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology (Berl) 1997;132:169–180.

    Article  CAS  Google Scholar 

  46. Saykin AJ, Shtasel DL, Gur RE, et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiat 1994;51:124–131.

    PubMed  CAS  Google Scholar 

  47. Tanila H, Mustonen K, Sallinen J, Scheinin M, Riekkinen P Jr. Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene. Eur J Neurosci 1999;11:599–603.

    Article  PubMed  CAS  Google Scholar 

  48. Weiner I, Feldon J. Facilitation of latent inhibition by haloperidol in rats. Psychopharmacology (Berl) 1987;91:248–253.

    CAS  Google Scholar 

  49. Joseph MHM, Jones SHS. Latent inhibition and blocking: further consideration of their construct validity as animal models of schizophrenia. Commentary on Ellenbroek and Cools “Animal models with construct validity for schizophrenia.” Behav Pharmacol 1991;2:521–526.

    Article  PubMed  Google Scholar 

  50. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997;88:615–626.

    Article  PubMed  CAS  Google Scholar 

  51. Le Pen G, Grottick AJ, Higgins GA, Martin JR, Jenck F, Moreau JL. Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophrenia. Behav Pharmacol 2000; 11:257–268.

    PubMed  Google Scholar 

  52. Bearden CE, Woodin MF, Wang PP, et al. The neurocognitive phenotype of the 22q1 1.2 deletion syndrome: selective deficit in visual-spatial memory. J Clin Exp Neuropsychol 2001; 23: 447–464.

    Article  PubMed  CAS  Google Scholar 

  53. Woodin M, Wang PP, Aleman D, McDonald-McGinn D, Zackai E, Moss E. Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet Med 2001; 3: 34–39.

    Article  PubMed  CAS  Google Scholar 

  54. Sobin C, Kiley-Brabeck K, Karayiorgou M. Lower pre-pulse inhibition in children with the 22q1 1 deletion syndrome. Am J Psychiatry 2005; 162:1090–1099.

    Article  PubMed  Google Scholar 

  55. Sobin C, Kiley-Brabeck K, Daniels S, Blundell M, Anyane-Yeboa K, Karayiorgou M. Networks of attention in children with the 22q11 deletion syndrome. Devel Neuropsychology 2004; 26:611–626.

    Article  Google Scholar 

  56. Liu H, Heath SC, Sobin C, et al. Genetic variation at the 22q1 1 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002;99:3717–3722.

    Article  PubMed  CAS  Google Scholar 

  57. Liu CM, Liu YL, Lin CY, et al. Significant association evidence of polymorphisms of PRODH/ DGCR6 with negative symptoms of schizophrenia. Am J Med Genet 2004; 130B, published online Sept. 15. Accessed October, 10, 2004.

    Google Scholar 

  58. Li T, Ma X, Sham PC, et al. vidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. Am J Med Genet 2004;129B:13–15.

    Article  PubMed  Google Scholar 

  59. Jacquet H, Raux G, Thibaut F, et al. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet 2002; 11:2243–2249.

    Article  PubMed  CAS  Google Scholar 

  60. Shifman S, Bronstein M, Sternfeld M, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002;71:1296–1302.

    Article  PubMed  CAS  Google Scholar 

  61. Chen X, Wang X, O’Neill AF, Walsh D, Kendler KS. Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiat 2004;9:962–967.

    Article  CAS  Google Scholar 

  62. Gogos JA, Santha M, Takacs Z, et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat Genet 1999;21:434–439.

    Article  PubMed  CAS  Google Scholar 

  63. Jacquet H, Berthelot J, Bonnemains C, et al. The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene. J Med Genet 2003;40:e7.

    Article  PubMed  CAS  Google Scholar 

  64. Chee M, Yang R, Hubbell E, et al. Accessing genetic information with high-density DNA arrays. Science 1996;274:610–614.

    Article  PubMed  CAS  Google Scholar 

  65. Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ. High density synthetic oligonucleotide arrays. Nat Genet 1999;21:20–24.

    Article  PubMed  CAS  Google Scholar 

  66. Lockhart DJ, Winzeler EA. Genomics, gene expression and DNA arrays. Nature 2000;405: 827–836.

    Article  PubMed  CAS  Google Scholar 

  67. Paterlini M, Zakharenk SS, Lai WS, et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nature Neuroscience, 2005;8:1586–1594.

    Article  PubMed  CAS  Google Scholar 

  68. Seeman P. Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1:133–152.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Gogos, J.A., Karayiorgou, M. (2006). Genetic Mouse Models of Psychiatric Disorders. In: Fisch, G.S., Flint, J. (eds) Transgenic and Knockout Models of Neuropsychiatric Disorders. Contemporary Clinical Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59745-058-4_9

Download citation

Publish with us

Policies and ethics