Advertisement

Susceptibility Genes for Schizophrenia: Mutant Models, Endophenotypes and Psychobiology

  • Colm M. P. O’TuathaighEmail author
  • Lieve Desbonnet
  • Paula M. Moran
  • John L. Waddington
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 12)

Abstract

Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models.

Keywords

Schizophrenia Psychotic illness Susceptibility gene Mutant model Phenotype Gene × environment interaction 

Notes

Acknowledgments

The authors’ studies are supported by Science Foundation Ireland Principal Investigator grant 07/IN.1/B960 and Health Research Board of Ireland Postdoctoral Fellowship PD/2007/20.

References

  1. Abazyan B, Nomura J, Kannan G et al (2010) Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry 68:1172–1181PubMedGoogle Scholar
  2. Accortt EE, Freeman MP, Allen JJ (2008) Women and major depressive disorder: clinical perspectives on causal pathways. J Womens Health 17:1583–1590Google Scholar
  3. Adler CM, Malhotra AK, Elman I et al (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649PubMedGoogle Scholar
  4. Allen NC, Bagade S, McQueen MB et al (2008) Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 40:827–834PubMedGoogle Scholar
  5. Almond SL, Fradley RL, Armstrong EJ et al (2006) Behavioral and biochemical characterization of a mutant mouse strain lacking D-amino acid oxidase activity and its implications for schizophrenia. Mol Cell Neurosci 32:324–334PubMedGoogle Scholar
  6. Amann LC, Gandal MJ, Halene TB et al (2010) Mouse behavioral endophenotypes for schizophrenia. Brain Res Bull 83:147–161PubMedGoogle Scholar
  7. Arguello PA, Gogos JA (2006) Modeling madness in mice: one piece at a time. Neuron 52:179–196PubMedGoogle Scholar
  8. Arguello PA, Gogos JA (2010) Cognition in mouse models of schizophrenia susceptibility genes. Schizophr Bull 36:289–300PubMedGoogle Scholar
  9. Arseneault L, Cannon M, Witton J et al (2004) Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 184:110–117PubMedGoogle Scholar
  10. Ayhan Y, Sawa A, Ross CA (2009) Animal models of gene-environment interactions in schizophrenia. Behav Brain Res 204:274–281PubMedGoogle Scholar
  11. Ayhan Y, Abazyan B, Nomura J et al (2011) Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders. Mol Psychiatry 16:293–306PubMedGoogle Scholar
  12. Babovic D, O’Tuathaigh CM, O’Connor AM et al (2008) Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase. Neuroscience 155:1021–1029PubMedGoogle Scholar
  13. Babovic D, O’Tuathaigh CM, O’Sullivan GJ et al (2007) Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice. Behav Brain Res 183:236–239PubMedGoogle Scholar
  14. Ballard TM, Pauly-Evers M, Higgins GA et al (2002) Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. J Neurosci 22:6713–6723PubMedGoogle Scholar
  15. Balu DT, Coyle JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35:848–870PubMedGoogle Scholar
  16. Barros CS, Calabrese B, Chamero P et al (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 106:4507–4512PubMedGoogle Scholar
  17. Bassett AS, Scherer SW, Brzustowicz LM (2010) Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry 167:899–914PubMedGoogle Scholar
  18. Basu AC, Tsai GE, Ma CL et al (2009) Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry 14:719–727PubMedGoogle Scholar
  19. Bauer D, Gupta D, Harotunian V et al (2008) Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr Res 104:108–120PubMedGoogle Scholar
  20. Bay-Richter C, O’Tuathaigh CM, O’Sullivan G et al (2009) Enhanced latent inhibition in dopamine receptor-deficient mice is sex-specific for the D1 but not D2 receptor subtype: implications for antipsychotic drug action. Int J Neuropsychopharmacol 17:1–12Google Scholar
  21. Beaulieu JM, Sotnikova TD, Yao WD et al (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci U S A 101:5099–5104PubMedGoogle Scholar
  22. Beaulieu JM, Sotnikova TD, Marion S (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122:261–273PubMedGoogle Scholar
  23. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347PubMedGoogle Scholar
  24. Belforte JE, Zsiros V, Sklar ER et al (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83PubMedGoogle Scholar
  25. Ben Abdallah NM, Fuss J, Trusel M et al (2011) The puzzle box as a simple and efficient behavioral test for exploring impairments of general cognition and executive functions in mouse models of schizophrenia. Exp Neurol 227:42–52PubMedGoogle Scholar
  26. Benneyworth MA, Basu AC, Coyle JT (2011) Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function. Psychopharmacology 213:143–153PubMedGoogle Scholar
  27. Bertram L (2008) Genetic research in schizophrenia: new tools and future perspectives. Schizophr Bull 34:806–812PubMedGoogle Scholar
  28. Bhardwaj SK, Baharnoori M, Sharif-Askari B et al (2009) Behavioral characterization of dysbindin-deficient sandy mice. Behav Brain Res 197:435–441PubMedGoogle Scholar
  29. Bjarnadottir M, Misner DL, Haverfield-Gross S et al (2007) Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1 ± knock-outs compared with wild-type mice. J Neurosci 27:4519–4529PubMedGoogle Scholar
  30. Boucher AA, Arnold JC, Duffy L et al (2007a) Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology 192:325–336Google Scholar
  31. Boucher AA, Hunt GE, Karl T et al (2007b) Heterozygous neuregulin 1 mice display greater baseline and Delta(9)-tetrahydrocannabinol-induced c-Fos expression. Neuroscience 149:861–70Google Scholar
  32. Boucher AA, Hunt GE, Micheau J et al (2010) The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. Int J Neuropsychopharmacol 12:1–13Google Scholar
  33. Braff D, Schork NJ, Gottesman II (2007) Endophenotyping schizophrenia. Am J Psychiatry 164:705–707PubMedGoogle Scholar
  34. Brigman JL, Graybeal C, Holmes A (2010) Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia. Front Neurosci 4:13PubMedGoogle Scholar
  35. Brody SA, Dulawa SC, Conquet F (2004) Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors. Mol Psychiatry 9:35–41PubMedGoogle Scholar
  36. Brown AS, Begg MD, Gravenstein S et al (2004) Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 61:774–780Google Scholar
  37. Burmeister M (1999) Basic concepts in the study of diseases with complex genetics. Biol Psychiatry 45:522–532PubMedGoogle Scholar
  38. Burmeister M, McInnis MG, Zöllner S (2008) Psychiatric genetics: progress amid controversy. Nat Rev Genet 9:527–540PubMedGoogle Scholar
  39. Burrows EL, McOmish CE, Hannan AJ (2011) Gene-environment interactions and construct validity in preclinical models of psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 35:1376–1382PubMedGoogle Scholar
  40. Cagniard B, Balsam PD, Brunner D et al (2006) Mice with chronically elevated dopamine exhibit enhanced motivation, but not learning, for a food reward. Neuropsychopharmacology 31:1362–1370PubMedGoogle Scholar
  41. Cannon TD, van Erp TG, Bearden CE et al (2003) Early and late neurodevelopmental influences in the prodrome to schizophrenia: contributions of genes, environment, and their interactions. Schizophr Bull 29:653–669PubMedGoogle Scholar
  42. Caspi A, Moffitt TE, Cannon M et al (2005) Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 57:1117–1127PubMedGoogle Scholar
  43. Chen YW, Lai WS (2011) Behavioral phenotyping of v-akt murine thymoma viral oncogene homolog 1-deficient mice reveals a sex-specific prepulse inhibition deficit in females that can be partially alleviated by glycogen synthase kinase-3 inhibitors but not by antipsychotics. Neuroscience 174:178–189PubMedGoogle Scholar
  44. Chen YJ, Johnson MA, Lieberman MD et al (2007) Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci 28:6872–6883Google Scholar
  45. Chourbaji S, Vogt MA, Fumagalli F et al (2008) AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J 22:3129–3134PubMedGoogle Scholar
  46. Chubb JE, Bradshaw NJ, Soares DC (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64PubMedGoogle Scholar
  47. Clancy B, Finlay BL, Darlington RB et al (2007) Extrapolating brain development from experimental species to humans. Neurotoxicology 28:931–937PubMedGoogle Scholar
  48. Clapcote SJ, Lipina TV, Millar JK et al (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402PubMedGoogle Scholar
  49. Costa RM, Gutierrez R, de Araujo IE et al (2007) Dopamine levels modulate the updating of tastant values. Genes Brain Behav 6:314–320PubMedGoogle Scholar
  50. Cox MM, Tucker AM, Tang J et al (2009) Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6 J genetic background. Genes Brain Behav 8:390–397PubMedGoogle Scholar
  51. Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384PubMedGoogle Scholar
  52. Craddock N, Owen MJ, O’Donovan MC (2006) The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol Psychiatry 11:446–458PubMedGoogle Scholar
  53. Deakin IH, Law AJ, Oliver PL et al (2009) Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport 20:1523–1528PubMedGoogle Scholar
  54. DeRosse P, Hodgkinson CA, Lencz T et al (2007) Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol Psychiatry 61:1208–1210PubMedGoogle Scholar
  55. Desbonnet L, Waddington JL, O’Tuathaigh CM (2009) Mice mutant for genes associated with schizophrenia: common phenotype or distinct endophenotypes? Behav Brain Res 204:258–273PubMedGoogle Scholar
  56. DeSteno DA, Schmauss C (2009) A role for dopamine D2 receptors in reversal learning. Neuroscience 162:118–127Google Scholar
  57. Devito LM, Balu DT, Kanter BR et al (2011) Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology. Genes Brain Behav 10:210–222PubMedGoogle Scholar
  58. Dinan TG (2010) MicroRNAs as a target for novel antipsychotics: a systematic review of an emerging field. Int J Neuropsychopharmacol 23:1–10Google Scholar
  59. Drew MR, Simpson EH, Kellendonk C et al (2009) Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing. J Neurosci 27:7731–7739Google Scholar
  60. Duan X, Chang JH, Ge S et al (2007) Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130:1146–1158PubMedGoogle Scholar
  61. Duffy L, Cappas E, Scimone A et al (2008) Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin 1. Behav Neurosci 122:748–759PubMedGoogle Scholar
  62. Duffy L, Cappas E, Lai D et al (2010) Cognition in transmembrane domain neuregulin 1 mutant mice. Neuroscience 170:800–807PubMedGoogle Scholar
  63. Duncan GE, Moy SS, Perez A et al (2004) Deficits in senosrimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507–519PubMedGoogle Scholar
  64. Duncan GE, Moy SS, Lieberman JA et al (2006) Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function. Psychopharmacology 184:190–200PubMedGoogle Scholar
  65. El-Ghundi M, O’Dowd BF, George SR (2007) Insights into the role of dopamine receptor systems in learning and memory. Rev Neurosci 18:37–66PubMedGoogle Scholar
  66. Emamian ES, Hall D, Birnbaum MJ (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36:131–137PubMedGoogle Scholar
  67. Etherton MR, Blaiss CA, Powell CM et al (2009) Mouse neurexin-1 alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci USA 106:17998–18003PubMedGoogle Scholar
  68. Farh KK, Grimson A, Jan C et al (2005) The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310:1817–1821PubMedGoogle Scholar
  69. Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35:528–548PubMedGoogle Scholar
  70. Fazzari P, Paternain AV, Valiente M et al (2010) Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464:1376–1380PubMedGoogle Scholar
  71. Feng YQ, Zhou ZY, He X et al (2008) Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. Schizophr Res 106:218–228PubMedGoogle Scholar
  72. Feyder M, Wiedholz L, Sprengel R et al (2007) Impaired associative fear learning in mice with complete loss or haploinsufficiency of AMPA GluR1 receptors. Front Behav Neurosci 1:4PubMedGoogle Scholar
  73. Fitzgerald PJ, Barkus C, Feyder M et al (2010) Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder? Neurobiol Dis 40:608–621PubMedGoogle Scholar
  74. Fradley RL, O’Meara GF, Newman RJ et al (2005) STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating. Behav Brain Res 163:257–264PubMedGoogle Scholar
  75. Gainetdinov RR (2008) Dopamine transporter mutant mice in experimental neuropharmacology. Naunyn Schmiedebergs Arch Pharmacol 377:301–313PubMedGoogle Scholar
  76. Gajendran N, Kapfhammer JP, Lain E et al (2009) Neuregulin signaling is dispensable for NMDA- and GABA(A)-receptor expression in the cerebellum in vivo. J Neurosci 29:2404–2413PubMedGoogle Scholar
  77. Garbett KA, Horváth S, Ebert PJ et al (2010) Novel animal models for studying complex brain disorders: BAC-driven miRNA-mediated in vivo silencing of gene expression. Mol Psychiatry 15:987–995PubMedGoogle Scholar
  78. Gill M, Donohoe G, Corvin A (2009) What have the genomics ever done for psychoses? Psychol Med 40:529–540PubMedGoogle Scholar
  79. Giros B, Jaber M, Jones SR et al (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612PubMedGoogle Scholar
  80. Glickstein SB, Hof PR, Schmauss C (2002) Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits. J Neurosci 22:5619–5629PubMedGoogle Scholar
  81. Gogos JA, Morgan M, Luine V et al (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 95:9991–9996PubMedGoogle Scholar
  82. Goodwin RD, Fergusson DM, Horwood LJ (2004) Panic attacks and psychoticism. Am J Psychiatry 161:88–92PubMedGoogle Scholar
  83. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and stategic intentions. Am J Psychiatry 160:636–645PubMedGoogle Scholar
  84. Gray L, Hannan AJ (2007) Dissecting cause and effect in the pathogenesis of psychiatric disorders: genes, environment and behaviour. Curr Mol Med 7:470–478PubMedGoogle Scholar
  85. Gray L, van den Buuse M, Scarr E et al (2009) Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation. Int J Neuropsychopharmacol 12:45–60PubMedGoogle Scholar
  86. Grozeva D, Kirov G, Ivanov D et al (2010) Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry 67:318–327PubMedGoogle Scholar
  87. Guo X, Hamilton PJ, Reish NJ et al (2009) Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of schizophrenia. Neuropsychopharmacology 34:1658–1672Google Scholar
  88. Haasio K, Huotari M, Nissinen E (2003) Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice. J Appl Toxicol 23:213–219PubMedGoogle Scholar
  89. Hajós M, Rogers BN (2010) Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr Pharm Des 16:538–554PubMedGoogle Scholar
  90. Halberstadt AL, Geyer MA (2009) Habituation and sensitization of acoustic startle: opposite influences of dopamine D1 and D2 family receptors. Neurobiol Learn Mem 92:243–248PubMedGoogle Scholar
  91. Hall FS, Sora I, Uhl GR (2003) Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice. Neuropsychopharmacology 28:620–628PubMedGoogle Scholar
  92. Harrison PJ, Law AJ (2006) Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 60:132–140PubMedGoogle Scholar
  93. Harrison PJ, Tunbridge EM (2008) Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33:3037–3045PubMedGoogle Scholar
  94. Harvey PD, Wingo AP, Burdick KE, Baldesarini RJ (2010) Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord 12:364–375PubMedGoogle Scholar
  95. Hashimoto A, Yoshikawa M, Niwa A et al (2005) Mice lacking D-amino acid oxidase activity display marked attenuation of stereotypy and ataxia induced by MK-801. Brain Res 1033:210–215PubMedGoogle Scholar
  96. Hattori S, Murotani T, Matsuzaki S et al (2008) Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Biochem Biophys Res Commun 373:298–302PubMedGoogle Scholar
  97. Hennah W, Porteous D (2009) The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS One 4:e4906PubMedGoogle Scholar
  98. Hennah W, Thomson P, McQuillin A et al (2009) DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry 14:865–873PubMedGoogle Scholar
  99. Henquet C, Murray R, Linszen D, van Os J (2005) The environment and schizophrenia: the role of cannabis use. Schizophr Bull 31:608–612Google Scholar
  100. Hikida T, Jaaro-Peled H, Seshadri S et al (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci USA 104:14501–14506PubMedGoogle Scholar
  101. Hironaka N, Ikeda K, Sora I et al (2004) Food-reinforced operant behavior in dopamine transporter knockout mice: enhanced resistance to extinction. Ann N Y Acad Sci 1025:140–145PubMedGoogle Scholar
  102. Holmes A, Lachowicz JE, Sibley DR (2004) Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes. Neuropharmacology 47:1117–1134PubMedGoogle Scholar
  103. Huotari M, Santha M, Lucas LR et al (2002) Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. J Pharmacol Exp Ther 303:1309–1316PubMedGoogle Scholar
  104. Hur EM, Zhou FQ (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11:539–551PubMedGoogle Scholar
  105. Ibi D, Nagai T, Koike H et al (2010) Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. Behav Brain Res 206:32–37PubMedGoogle Scholar
  106. Ichtchenko K, Hata Y, Nguyen T et al (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81:435–443PubMedGoogle Scholar
  107. Ikeda M, Aleksic B, Kirov G et al (2010) Copy number variation in schizophrenia in the Japanese population. Biol Psychiatry 67:283–286PubMedGoogle Scholar
  108. International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241Google Scholar
  109. International Schizophrenia Consortium, Purcell SM, Wray NR et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–52Google Scholar
  110. Javitt DC, Balla A, Burch S et al (2004) Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists. Neuropsychopharmacology 29:300–307PubMedGoogle Scholar
  111. Jentsch JD, Trantham-Davidson H, Jairl C et al (2009) Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology 34:2601–2608PubMedGoogle Scholar
  112. Ji Y, Yang F, Papaleo F et al (2009) Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci USA 106:19593–19598PubMedGoogle Scholar
  113. Johnstone M, Thomson PA, Hall J et al (2011) DISC1 in schizophrenia: genetic mouse models and human genomic imaging. Schizophr Bull 37:14–20PubMedGoogle Scholar
  114. Karayiorgou M, Gogos JA (2006) Schizophrenia genetics: uncovering positional candidate genes. Eur J Hum Genet 14:512–519PubMedGoogle Scholar
  115. Karl T, Duffy L, Scimone A et al (2007) Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav 6:677–687PubMedGoogle Scholar
  116. Karlsgodt KH, Robleto K, Trantham-Davidson H et al (2011) Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry 69:28–34PubMedGoogle Scholar
  117. Karlsson RM, Tanaka K, Heilig M et al (2008) Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol Psychiatry 64:810–814PubMedGoogle Scholar
  118. Karlsson RM, Tanaka K, Saksida LM et al (2009) Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 34:1578–1589PubMedGoogle Scholar
  119. Kato T, Kasai A, Mizuno M et al (2010) Phenotypic characterization of transgenic mice overexpressing neuregulin-1. PLoS One 5:e14185PubMedGoogle Scholar
  120. Kegeles LS, Abi-Dargham A, Zea-Ponce Y et al (2000) Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 48:627–640PubMedGoogle Scholar
  121. Kember RL, Fernandes C, Tunbridge EM et al (2010) A B2 SINE insertion in the Comt1 gene (Comt1(B2i)) results in an overexpressing, behavior modifying allele present in classical inbred mouse strains. Genes Brain Behav 9:925–932PubMedGoogle Scholar
  122. Kim JY, Duan X, Liu CY et al (2009) DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63:761–773PubMedGoogle Scholar
  123. Kirby B, Waddington JL, O’Tuathaigh CMP (2010) Advancing a functional genomics for schizophrenia: psychopathological and cognitive phenotypes in mutants with gene disruption. Brain Res Bull 83:162–176PubMedGoogle Scholar
  124. Kirov G, Gumus D, Chen W et al (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 17:458–465PubMedGoogle Scholar
  125. Kirov G, Grozeva D, Norton N et al (2009a) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 18:1497–1503Google Scholar
  126. Kirov G, Rujescu D, Ingason A et al (2009b) Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 35:851–4Google Scholar
  127. Koike H, Arguello PA, Kvajo M et al (2006) Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci USA 103:3693–3697PubMedGoogle Scholar
  128. Knuesel I (2010) Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases. Prog Neurobiol 91:257–274PubMedGoogle Scholar
  129. Krivoy A, Fischel T, Weizman A (2008) The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol 18:395–405PubMedGoogle Scholar
  130. Kruzich PJ, Grandy DK (2004) Dopamine D2 receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice. BMC Neurosci 5:12PubMedGoogle Scholar
  131. Kvajo M, McKellar H, Arguello PA et al (2008) A mutation in mouse Disc 1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci USA 105:7076–7081PubMedGoogle Scholar
  132. Labrie V, Lipina T, Roder JC (2008) Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology 200:217–230PubMedGoogle Scholar
  133. Labrie V, Roder JC (2010) The involvement of the NMDA receptor d-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci Biobehav Rev 34:351–372PubMedGoogle Scholar
  134. Laviola G, Adriani W, Gaudino C et al (2006) Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereotypies in reeler mutant mice. Psychopharmacology 187:331–344PubMedGoogle Scholar
  135. Levinson DF, Duan J, Oh S et al (2011) Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 168:302–316PubMedGoogle Scholar
  136. Lewis CM, Levinson DF, Wise LH et al (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 73:34–48PubMedGoogle Scholar
  137. Li W, Zhang Q, Oiso N et al (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 35:84–89PubMedGoogle Scholar
  138. Li W, Zhou Y, Jentsch JD et al (2007) Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci USA 104:18280–18285PubMedGoogle Scholar
  139. Li B, Devidze N, Barengolts D et al (2009) NMDA receptor phosphorylation at a site affected in schizophrenia controls synaptic and behavioral plasticity. J Neurosci 29:11965–11972PubMedGoogle Scholar
  140. Li Z, Mulligan MK, Wang X (2010) A transposon in comt generates mRNA variants and causes widespread expression and behavioral differences among mice. PLoS One 5:e12181PubMedGoogle Scholar
  141. Lipina TV, Niwa M, Jaaro-Peled H et al (2010) Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia. Genes Brain Behav 9:777–789PubMedGoogle Scholar
  142. Lijam N, Paylor R, McDonald MP et al (1997) Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell 90:895–905PubMedGoogle Scholar
  143. Long JM, LaPorte P, Paylor R et al (2004) Expanded characterization of the social interaction abnormalities in mice lacking Dvl1. Genes Brain Behav 3:51–62PubMedGoogle Scholar
  144. Long JM, LaPorte P, Merscher S et al (2006) Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics 7:247–257PubMedGoogle Scholar
  145. Long LE, Chesworth R, Arnold JC et al (2010) A follow-up study: acute behavioural effects of Delta (9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice. Psychopharmacology 211:277–289PubMedGoogle Scholar
  146. Low NC, Hardy J (2007) What is a schizophrenic mouse? Neuron 54:348–349PubMedGoogle Scholar
  147. Maekawa M, Okamura T, Kasai N et al (2005) D-amino-acid oxidase is involved in d-serine-induced nephrotoxicity. Chem Res Toxicol 18:1678–1682PubMedGoogle Scholar
  148. Malhotra AK, Adler CM, Kennison SD et al (1997a) Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biol Psychiatry 42:664–668PubMedGoogle Scholar
  149. Meechan DW, Maynard TM, Gopalakrishna D et al (2007a) When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. Gene Expr 13:299–310PubMedGoogle Scholar
  150. Manolio TA, Rodriguez LL, Brooks L et al (2007) New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 39:1045–1051PubMedGoogle Scholar
  151. Malhotra AK, Pinals DA, Adler CM et al (1997b) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150PubMedGoogle Scholar
  152. Mao Y, Ge X, Frank CL et al (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136:1017–1031PubMedGoogle Scholar
  153. Mathews TA, John CE, Lapa GB (2006) No role of the dopamine transporter in acute ethanol effects on striatal dopamine dynamics. Synapse 60:288–294PubMedGoogle Scholar
  154. Meechan DW, Maynard TM, Gopalakrishna D et al (2007b) When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. Gene Expr 13:299–310PubMedGoogle Scholar
  155. Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9:437–452PubMedGoogle Scholar
  156. Meyer U, Feldon J, Fatemi SH (2009) In vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev 33:1061–1079PubMedGoogle Scholar
  157. Miller BH, Wahlestedt C (2010) MicroRNA dysregulation in psychiatric disease. Brain Res 1338:89–99PubMedGoogle Scholar
  158. Miyamoto Y, Nabeshima T (2002) Analysis of neuronal functions in mice lacking the NMDA receptor epsilon 1 subunit. Nippon Yakurigaku Zasshi 119:327–335PubMedGoogle Scholar
  159. Mohn AR, Gainetdinov RR, Caron MG et al (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427–436PubMedGoogle Scholar
  160. Moore TH, Zammit S, Lingford-Hughes A (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328PubMedGoogle Scholar
  161. Muir WJ, Pickard BS, Blackwood DH (2008) Disrupted-in-Schizophrenia-1. Curr Psychiatry Rep 10:140–147PubMedGoogle Scholar
  162. Murotani T, Ishizuka T, Hattori S et al (2007) High dopamine turnover in the brains of Sandy mice. Neurosci Lett 421:47–51PubMedGoogle Scholar
  163. Myin-Germeys I, Delespaul P, van Os J (2005) Behavioural sensitization to daily life stress in psychosis. Psychol Med 35:733–741PubMedGoogle Scholar
  164. Myin-Germeys I, Oorschot M, Collip D et al (2009) Experience sampling research in psychopathology: opening the black box of daily life. Psychol Med 39:1533–1547PubMedGoogle Scholar
  165. Niwa M, Kamiya A, Murai R et al (2010) Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 65:480–489PubMedGoogle Scholar
  166. Numakawa T, Yagasaki Y, Ishimoto T (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13:2699–2708PubMedGoogle Scholar
  167. Ognibene E, Adriani W, Macrì S et al (2007) Neurobehavioural disorders in the infant reeler mouse model: interaction of genetic vulnerability and consequences of maternal separation. Behav Brain Res 177:142–149PubMedGoogle Scholar
  168. Oliver PL, Davies KE (2009) Interaction between environmental and genetic factors modulates schizophrenic endophenotypes in the Snap-25 mouse mutant blind-drunk. Hum Mol Genet 18:4576–4589PubMedGoogle Scholar
  169. O’Sullivan, GJ, O’Tuathaigh C, Tomiyama K, Koshikawa N, Waddington JL (2010) Dopamine receptor subtypes and behaviour: from psychopharmacology to mutant models. In: Neve K (ed) The dopamine receptors, pp 323–371. Humana Press, TotowaGoogle Scholar
  170. O’Tuathaigh CM, O’Sullivan GJ, Kinsella A et al (2006) Sexually dimorphic changes in the exploratory and habituation profiles of heterozygous neuregulin-1 knockout mice. Neuroreport 17:79–83PubMedGoogle Scholar
  171. O’Tuathaigh CMP, Babovic D, O’Meara G et al (2007a) Susceptibility genes for schizophrenia: phenotypic characterisation of mutant models. Neurosci Biobehav Rev 31:60–78Google Scholar
  172. O’Tuathaigh CM, Babovic D, O’Sullivan GJ et al (2007b) Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1. Neuroscience 147:18–27Google Scholar
  173. O’Tuathaigh CM, O’Connor AM, O’Sullivan GJ et al (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 32:462–466PubMedGoogle Scholar
  174. O’Tuathaigh CM, Desbonnet L, Waddington JL (2009) Neuregulin-1 signalling in schizophrenia: ‘Jack of all trades’ or master of some? Expert Rev Neurother 9:1–3PubMedGoogle Scholar
  175. O’Tuathaigh CMP, Waddington JL (2010) Mutant mouse models: phenotypic relationships to domains of psychopathology and pathobiology in schizophrenia. Schizophr Bull 36:243–245PubMedGoogle Scholar
  176. O’Tuathaigh CMP, Kirby BP, Moran PM et al (2010a) Mutant mouse models: genotype-phenotype relationships to negative symptoms in schizophrenia. Schizophr Bull 36:271–288Google Scholar
  177. O’Tuathaigh CMP, Harte M, Tighe O et al (2010b) Schizophrenia-related endophenotypes in heterozygous neuregulin-1 ‘knockout’ mice: NMDA-receptor antagonist effects, neurochemistry and brain structure. Eur J Neurosci 31:349–58Google Scholar
  178. O’Tuathaigh CM, Hryniewiecka M, Behan A et al (2010c) Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT knockout mice: Impact on phenotypes relevant to psychosis. Neuropsychopharmacology 35:2262–2273Google Scholar
  179. Owen MJ, Craddock N, O’Donovan MC (2010) Suggestion of roles for both common and rare risk variants in genome-wide studies of schizophrenia. Arch Gen Psychiatry 67:667–673PubMedGoogle Scholar
  180. Papaleo F, Crawley JN, Song J et al (2008) Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci 28:8709–8723PubMedGoogle Scholar
  181. Papaleo F, Yang F, Garcia S et al (2012) Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 17:85–98PubMedGoogle Scholar
  182. Patil ST, Zhang L, Martenyi F et al (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13:1102–1107PubMedGoogle Scholar
  183. Paylor R, Glaser B, Mupo A et al (2006) Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc Natl Acad Sci USA 103:7729–7734PubMedGoogle Scholar
  184. Pilowsky LS, Bressan RA, Stone JM et al (2007) First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 11:118–119Google Scholar
  185. Pinard E, Alanine A, Alberati D et al (2010) Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia. J Med Chem 53:4603–4614PubMedGoogle Scholar
  186. Pletnikov MV, Ayhan Y, Nikolskaia O et al (2008) Inducible expression of mutant human DISC1 in mice is associated with brain and behavioural abnormalities reminiscent of schizophrenia. Mol Psychiatry 13:173–186PubMedGoogle Scholar
  187. Ralph RJ, Varty GB, Kelly MA et al (1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci 19:4627–4633PubMedGoogle Scholar
  188. Ralph-Williams RJ, Lehmann-Masten V, Otero-Corchon V et al (2002) Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knockout mice. J Neurosci 22:9604–9611PubMedGoogle Scholar
  189. Rimer M, Barrett DW, Maldonado MA, Vock VM et al (2005) Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition. Neuroreport 16:271–275PubMedGoogle Scholar
  190. Rodriguiz RM, Chu R, Caron MG et al (2004) Aberrant responses in social interaction of dopamine transporter knockout mice. Behav Brain Res 148:185–198PubMedGoogle Scholar
  191. Ross CA, Margolis RL, Reading SA et al (2006) Neurobiology of schizophrenia. Neuron 52:139–153PubMedGoogle Scholar
  192. Rujescu D, Ingason A, Cichon S et al (2009) Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 18:988–996PubMedGoogle Scholar
  193. Sagata N, Iwaki A, Aramaki T et al (2010) Comprehensive behavioural study of GluR4 knockout mice: implication in cognitive function. Genes Brain Behav 9:899–909PubMedGoogle Scholar
  194. Savelieva KV, Caudle WM, Findlay GS (2002) Decreased ethanol preference and consumption in dopamine transporter female knock-out mice. Alcohol Clin Exp Res 26:758–764PubMedGoogle Scholar
  195. Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58PubMedGoogle Scholar
  196. Shen S, Lang B, Nakamoto C et al (2008) Schizophrenia-related neural and behavioural phenotypes in transgenic mice expressing truncated DISC1. J Neurosci 28:10893–10904PubMedGoogle Scholar
  197. Shu T, Ayala R, Nguyen MD et al (2004) Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron 44:263–277PubMedGoogle Scholar
  198. Singer P, Boison D, Möhler H (2007) Enhanced recognition memory following glycine transporter 1 deletion in forebrain neurons. Behav Neurosci 121:815–825PubMedGoogle Scholar
  199. Singer P, Feldon J, Yee BK et al (2009) Are DBA/2 mice associated with schizophrenia-like endophenotypes? A behavioural contrast with C57BL/6 mice. Psychopharmacology 206:677–698PubMedGoogle Scholar
  200. Singer P, Boison D, Möhler H et al (2011) Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice. Eur Neuropsychopharmacol 21:401–413PubMedGoogle Scholar
  201. Smith RE, Haroutunian V, Davis KL et al (2001) Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry 158:1393–1399PubMedGoogle Scholar
  202. Stark KL, Xu B, Bagchi A et al (2008) Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 40:751–760PubMedGoogle Scholar
  203. Stefansson H, Sigurdsson E, Steinthorsdottir V et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892PubMedGoogle Scholar
  204. Steinberg S, Mors O, Børglum AD et al (2011) Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry 16:59–66PubMedGoogle Scholar
  205. Stone JM, Morrison PD, Pilowsky LS (2007) Glutamate and dopamine dysregulation in schizophrenia-a synthesis and selective review. J Psychopharmacol 21:440–452PubMedGoogle Scholar
  206. Szeszko PR, Hodgkinson CA, Robinson DG et al (2008) DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia. Biol Psychol 79:103–110PubMedGoogle Scholar
  207. Takao K, Yamasaki N, Miyakawa T (2007) Impact of brain-behavior phenotyping of genetically-engineered mice on research of neuropsychiatric disorders. Neurosci Res 58:124–132PubMedGoogle Scholar
  208. Takao K, Toyama K, Nakanishi K et al (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 1:11PubMedGoogle Scholar
  209. Takashima A (2009) Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: role of GSK-3beta in adult brain. J Pharmacol Sci 109:174–178PubMedGoogle Scholar
  210. Talbot K (2009) The sandy (sdy) mouse: a dysbindin-1 mutant relevant to schizophrenia research. Prog Brain Res 179:87–94PubMedGoogle Scholar
  211. Tammimäki A, Forsberg MM, Karayiorgou M et al (2008) Increase in free choice oral ethanol self-administration in catechol-o-methyltransferase gene-disrupted male mice. Basic Clin Pharmacol Toxicol 103:297–304PubMedGoogle Scholar
  212. Tandon R, Nasrallah HA, Keshavan MS (2009) Schizophrenia, “just the facts” 4 Clinical features and conceptualization. Schizophr Res 110:1–23PubMedGoogle Scholar
  213. Tang J, LeGros RP, Louneva N et al (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum Mol Genet 18:3851–3863PubMedGoogle Scholar
  214. Taylor SB, Taylor AR, Markham JA et al (2011) Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. Physiol Behav 104:205–214PubMedGoogle Scholar
  215. Thompson BL, Levitt P (2010) The clinical-basic interface in defining pathogenesis in disorders of neurodevelopmental origin. Neuron 67:702–712PubMedGoogle Scholar
  216. Tsai G, Ralph-Williams RJ, Martina M et al (2004) Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc Natl Acad Sci U S A 101:8485–8490PubMedGoogle Scholar
  217. Tsien JZ (2000) Linking Hebb’s coincidence-detection to memory formation. Curr Opin Neurobiol 10:266–273PubMedGoogle Scholar
  218. Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 60:141–151PubMedGoogle Scholar
  219. Tuominen HJ, Tiihonen J, Wahlbeck K (2005) Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res 72:225–234PubMedGoogle Scholar
  220. van den Buuse M, Wischhof L, Lee RX et al (2009) Neuregulin 1 hypomorphic mutant mice: enhanced baseline locomotor activity but normal psychotropic drug-induced hyperlocomotion and prepulse inhibition regulation. Int J Neuropsychopharmacol 12:1383–1393PubMedGoogle Scholar
  221. Van den Buuse M (2010) Modelling the positive symptoms of schizophrenia in genetically-modified mice: pharmacology and methodology aspects. Schizophr Bull 36:246–270PubMedGoogle Scholar
  222. van Os J, Kenis G, Rutten BP (2010) The environment and schizophrenia. Nature 468:203–212PubMedGoogle Scholar
  223. Waddington JL, O’Tuathaigh C, O’Sullivan G et al (2005) Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology-molecular biology interface. Psychopharmacology 181:611–638PubMedGoogle Scholar
  224. Waddington JL, Corvin AP, Donohoe G, O’Tuathaigh CMP, Mitchell KJ, Gill M (2007) Functional genomics and schizophrenia: endophenotypes and mutant models. Psychiat Clin N Amer 30:365–399Google Scholar
  225. Waddington JL, Hennessy RJ, O’Tuathaigh CMP, Owoeye O, Russell V (2011) Schizophrenia and the lifetime trajectory of psychotic illness: developmental neuroscience and pathobiology, redux. In: Brown AS, Patterson PH (eds.) The Origins of Schizophrenia. Columbia University Press, New York (in press)Google Scholar
  226. Walsh T, McClellan JM, McCarthy SE et al (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543PubMedGoogle Scholar
  227. Walss-Bass C, Liu W, Lew DF et al (2006) A novel missense mutation in the transmembrane domain of neuregulin 1 is associated with schizophrenia. Biol Psychiatry 60:548–553PubMedGoogle Scholar
  228. Wang Y, Xu R, Sasaoka T et al (2000) Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J Neurosci 20:8305–8314PubMedGoogle Scholar
  229. Wang Q, Jaaro-Peled H, Sawa A (2008) How has DISC1 enabled drug discovery? Mol Cell Neurosci 37:187–195PubMedGoogle Scholar
  230. Wen L, Lu YS, Zhu XH et al (2010) Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA 107:1211–1216PubMedGoogle Scholar
  231. Weickert CS, Straub RE, McClintock BW et al (2004) Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 61:544–555PubMedGoogle Scholar
  232. Wiedholz LM, Owens WA, Horton RE et al (2008) Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors. Mol Psychiatry 13:631–640PubMedGoogle Scholar
  233. Xing B, Kong H, Meng X et al (2010) Dopamine D1 but not D3 receptor is critical for spatial learning and related signaling in the hippocampus. Neuroscience 169:1511–1519PubMedGoogle Scholar
  234. Xu R, Hranilovic D, Fetsko LA et al (2002) Dopamine D2S and D2L receptors may differentially contribute to the actions of antipsychotic and psychotic agents in mice. Mol Psychiatry 7:1075–1082PubMedGoogle Scholar
  235. Xu B, Roos JL, Levy S et al (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40:880–885PubMedGoogle Scholar
  236. Xu B, Woodroffe A, Rodriguez-Murillo L (2009) Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans. Proc Natl Acad Sci USA 106:16746–16751PubMedGoogle Scholar
  237. Yee BK, Balic E, Singer P et al (2006) Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile. J Neurosci 26:3169–3181PubMedGoogle Scholar
  238. Young JW, Crawford N, Kelly JS et al (2007) Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice. Eur Neuropsychopharmacol 17:145–155PubMedGoogle Scholar
  239. Young-Pearse TL, Bai J, Chang R et al (2007) A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci 27:14459–14469PubMedGoogle Scholar
  240. Zhang R, Su B (2008) MicroRNA regulation and the variability of human cortical gene expression. Nucleic Acids Res 36:4621–4628PubMedGoogle Scholar
  241. Zhang M, Ballard ME, Basso AM et al (2011) Behavioral characterization of a mutant mouse strain lacking D-amino acid oxidase activity. Behav Brain Res 217:81–87PubMedGoogle Scholar
  242. Zhou X, Nie Z, Roberts A et al (2010) Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. Hum Mol Genet 19:3797–3805PubMedGoogle Scholar
  243. Zhuang X, Oosting RS, Jones SR et al (2001) Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci U S A 98:1982–1987PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Colm M. P. O’Tuathaigh
    • 1
    • 2
    Email author
  • Lieve Desbonnet
    • 1
  • Paula M. Moran
    • 3
  • John L. Waddington
    • 1
  1. 1.Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublin 2Ireland
  2. 2.School of MedicineUniversity College CorkCorkIreland
  3. 3.School of PsychologyUniversity of NottinghamNottinghamUK

Personalised recommendations