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Susceptibility Genes for Schizophrenia: Mutant Models, Endophenotypes and Psychobiology

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Behavioral Neurogenetics

Part of the book series: Current Topics in Behavioral Neurosciences ((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.

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References

  • Abazyan B, Nomura J, Kannan G et al (2010) Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry 68:1172–1181

    PubMed  CAS  Google Scholar 

  • Accortt EE, Freeman MP, Allen JJ (2008) Women and major depressive disorder: clinical perspectives on causal pathways. J Womens Health 17:1583–1590

    Google Scholar 

  • 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 156:1646–1649

    PubMed  CAS  Google Scholar 

  • 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 40:827–834

    PubMed  CAS  Google Scholar 

  • 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 32:324–334

    PubMed  CAS  Google Scholar 

  • Amann LC, Gandal MJ, Halene TB et al (2010) Mouse behavioral endophenotypes for schizophrenia. Brain Res Bull 83:147–161

    PubMed  Google Scholar 

  • Arguello PA, Gogos JA (2006) Modeling madness in mice: one piece at a time. Neuron 52:179–196

    PubMed  CAS  Google Scholar 

  • Arguello PA, Gogos JA (2010) Cognition in mouse models of schizophrenia susceptibility genes. Schizophr Bull 36:289–300

    PubMed  Google Scholar 

  • Arseneault L, Cannon M, Witton J et al (2004) Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 184:110–117

    PubMed  Google Scholar 

  • Ayhan Y, Sawa A, Ross CA (2009) Animal models of gene-environment interactions in schizophrenia. Behav Brain Res 204:274–281

    PubMed  CAS  Google Scholar 

  • 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 16:293–306

    PubMed  CAS  Google Scholar 

  • 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 155:1021–1029

    PubMed  CAS  Google Scholar 

  • 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 183:236–239

    PubMed  CAS  Google Scholar 

  • 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 22:6713–6723

    PubMed  CAS  Google Scholar 

  • Balu DT, Coyle JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35:848–870

    PubMed  CAS  Google Scholar 

  • 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 106:4507–4512

    PubMed  CAS  Google Scholar 

  • 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 167:899–914

    PubMed  Google Scholar 

  • Basu AC, Tsai GE, Ma CL et al (2009) Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry 14:719–727

    PubMed  CAS  Google Scholar 

  • 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 104:108–120

    PubMed  Google Scholar 

  • 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 17:1–12

    Google Scholar 

  • 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 101:5099–5104

    PubMed  CAS  Google Scholar 

  • Beaulieu JM, Sotnikova TD, Marion S (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122:261–273

    PubMed  CAS  Google Scholar 

  • Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347

    PubMed  CAS  Google Scholar 

  • Belforte JE, Zsiros V, Sklar ER et al (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83

    PubMed  CAS  Google Scholar 

  • 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 227:42–52

    PubMed  Google Scholar 

  • Benneyworth MA, Basu AC, Coyle JT (2011) Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function. Psychopharmacology 213:143–153

    PubMed  CAS  Google Scholar 

  • Bertram L (2008) Genetic research in schizophrenia: new tools and future perspectives. Schizophr Bull 34:806–812

    PubMed  Google Scholar 

  • Bhardwaj SK, Baharnoori M, Sharif-Askari B et al (2009) Behavioral characterization of dysbindin-deficient sandy mice. Behav Brain Res 197:435–441

    PubMed  CAS  Google Scholar 

  • 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 27:4519–4529

    PubMed  CAS  Google Scholar 

  • Boucher AA, Arnold JC, Duffy L et al (2007a) Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology 192:325–336

    Google Scholar 

  • 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 149:861–70

    Google Scholar 

  • 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 12:1–13

    Google Scholar 

  • Braff D, Schork NJ, Gottesman II (2007) Endophenotyping schizophrenia. Am J Psychiatry 164:705–707

    PubMed  Google Scholar 

  • Brigman JL, Graybeal C, Holmes A (2010) Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia. Front Neurosci 4:13

    PubMed  Google Scholar 

  • Brody SA, Dulawa SC, Conquet F (2004) Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors. Mol Psychiatry 9:35–41

    PubMed  CAS  Google Scholar 

  • Brown AS, Begg MD, Gravenstein S et al (2004) Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 61:774–780

    Google Scholar 

  • Burmeister M (1999) Basic concepts in the study of diseases with complex genetics. Biol Psychiatry 45:522–532

    PubMed  CAS  Google Scholar 

  • Burmeister M, McInnis MG, Zöllner S (2008) Psychiatric genetics: progress amid controversy. Nat Rev Genet 9:527–540

    PubMed  CAS  Google Scholar 

  • Burrows EL, McOmish CE, Hannan AJ (2011) Gene-environment interactions and construct validity in preclinical models of psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 35:1376–1382

    PubMed  Google Scholar 

  • 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 31:1362–1370

    PubMed  CAS  Google Scholar 

  • 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 29:653–669

    PubMed  Google Scholar 

  • 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 57:1117–1127

    PubMed  CAS  Google Scholar 

  • 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 174:178–189

    PubMed  CAS  Google Scholar 

  • 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 28:6872–6883

    Google Scholar 

  • 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 22:3129–3134

    PubMed  CAS  Google Scholar 

  • Chubb JE, Bradshaw NJ, Soares DC (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64

    PubMed  CAS  Google Scholar 

  • Clancy B, Finlay BL, Darlington RB et al (2007) Extrapolating brain development from experimental species to humans. Neurotoxicology 28:931–937

    PubMed  Google Scholar 

  • Clapcote SJ, Lipina TV, Millar JK et al (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402

    PubMed  CAS  Google Scholar 

  • Costa RM, Gutierrez R, de Araujo IE et al (2007) Dopamine levels modulate the updating of tastant values. Genes Brain Behav 6:314–320

    PubMed  CAS  Google Scholar 

  • 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 8:390–397

    PubMed  CAS  Google Scholar 

  • Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    PubMed  CAS  Google Scholar 

  • 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 11:446–458

    PubMed  CAS  Google Scholar 

  • Deakin IH, Law AJ, Oliver PL et al (2009) Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport 20:1523–1528

    PubMed  CAS  Google Scholar 

  • DeRosse P, Hodgkinson CA, Lencz T et al (2007) Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol Psychiatry 61:1208–1210

    PubMed  CAS  Google Scholar 

  • Desbonnet L, Waddington JL, O’Tuathaigh CM (2009) Mice mutant for genes associated with schizophrenia: common phenotype or distinct endophenotypes? Behav Brain Res 204:258–273

    PubMed  CAS  Google Scholar 

  • DeSteno DA, Schmauss C (2009) A role for dopamine D2 receptors in reversal learning. Neuroscience 162:118–127

    CAS  Google Scholar 

  • Devito LM, Balu DT, Kanter BR et al (2011) Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology. Genes Brain Behav 10:210–222

    PubMed  CAS  Google Scholar 

  • Dinan TG (2010) MicroRNAs as a target for novel antipsychotics: a systematic review of an emerging field. Int J Neuropsychopharmacol 23:1–10

    Google Scholar 

  • Drew MR, Simpson EH, Kellendonk C et al (2009) Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing. J Neurosci 27:7731–7739

    Google Scholar 

  • Duan X, Chang JH, Ge S et al (2007) Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130:1146–1158

    PubMed  CAS  Google Scholar 

  • 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 122:748–759

    PubMed  Google Scholar 

  • Duffy L, Cappas E, Lai D et al (2010) Cognition in transmembrane domain neuregulin 1 mutant mice. Neuroscience 170:800–807

    PubMed  CAS  Google Scholar 

  • 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 153:507–519

    PubMed  CAS  Google Scholar 

  • 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 184:190–200

    PubMed  CAS  Google Scholar 

  • El-Ghundi M, O’Dowd BF, George SR (2007) Insights into the role of dopamine receptor systems in learning and memory. Rev Neurosci 18:37–66

    PubMed  CAS  Google Scholar 

  • Emamian ES, Hall D, Birnbaum MJ (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36:131–137

    PubMed  CAS  Google Scholar 

  • 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 106:17998–18003

    PubMed  CAS  Google Scholar 

  • Farh KK, Grimson A, Jan C et al (2005) The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310:1817–1821

    PubMed  CAS  Google Scholar 

  • Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35:528–548

    PubMed  Google Scholar 

  • Fazzari P, Paternain AV, Valiente M et al (2010) Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464:1376–1380

    PubMed  CAS  Google Scholar 

  • 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 106:218–228

    PubMed  Google Scholar 

  • 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 1:4

    PubMed  Google Scholar 

  • Fitzgerald PJ, Barkus C, Feyder M et al (2010) Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder? Neurobiol Dis 40:608–621

    PubMed  CAS  Google Scholar 

  • 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 163:257–264

    PubMed  CAS  Google Scholar 

  • Gainetdinov RR (2008) Dopamine transporter mutant mice in experimental neuropharmacology. Naunyn Schmiedebergs Arch Pharmacol 377:301–313

    PubMed  CAS  Google Scholar 

  • 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 29:2404–2413

    PubMed  CAS  Google Scholar 

  • 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 15:987–995

    PubMed  CAS  Google Scholar 

  • Gill M, Donohoe G, Corvin A (2009) What have the genomics ever done for psychoses? Psychol Med 40:529–540

    PubMed  Google Scholar 

  • Giros B, Jaber M, Jones SR et al (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612

    PubMed  CAS  Google Scholar 

  • Glickstein SB, Hof PR, Schmauss C (2002) Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits. J Neurosci 22:5619–5629

    PubMed  CAS  Google Scholar 

  • 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 95:9991–9996

    PubMed  CAS  Google Scholar 

  • Goodwin RD, Fergusson DM, Horwood LJ (2004) Panic attacks and psychoticism. Am J Psychiatry 161:88–92

    PubMed  Google Scholar 

  • Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and stategic intentions. Am J Psychiatry 160:636–645

    PubMed  Google Scholar 

  • Gray L, Hannan AJ (2007) Dissecting cause and effect in the pathogenesis of psychiatric disorders: genes, environment and behaviour. Curr Mol Med 7:470–478

    PubMed  CAS  Google Scholar 

  • 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 12:45–60

    PubMed  CAS  Google Scholar 

  • 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 67:318–327

    PubMed  Google Scholar 

  • 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 34:1658–1672

    Google Scholar 

  • Haasio K, Huotari M, Nissinen E (2003) Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice. J Appl Toxicol 23:213–219

    PubMed  CAS  Google Scholar 

  • Hajós M, Rogers BN (2010) Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr Pharm Des 16:538–554

    PubMed  Google Scholar 

  • Halberstadt AL, Geyer MA (2009) Habituation and sensitization of acoustic startle: opposite influences of dopamine D1 and D2 family receptors. Neurobiol Learn Mem 92:243–248

    PubMed  CAS  Google Scholar 

  • 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 28:620–628

    PubMed  Google Scholar 

  • Harrison PJ, Law AJ (2006) Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 60:132–140

    PubMed  CAS  Google Scholar 

  • 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 33:3037–3045

    PubMed  CAS  Google Scholar 

  • Harvey PD, Wingo AP, Burdick KE, Baldesarini RJ (2010) Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord 12:364–375

    PubMed  Google Scholar 

  • 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 1033:210–215

    PubMed  CAS  Google Scholar 

  • 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 373:298–302

    PubMed  CAS  Google Scholar 

  • Hennah W, Porteous D (2009) The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS One 4:e4906

    PubMed  Google Scholar 

  • Hennah W, Thomson P, McQuillin A et al (2009) DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry 14:865–873

    PubMed  CAS  Google Scholar 

  • Henquet C, Murray R, Linszen D, van Os J (2005) The environment and schizophrenia: the role of cannabis use. Schizophr Bull 31:608–612

    Google Scholar 

  • 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 104:14501–14506

    PubMed  CAS  Google Scholar 

  • 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 1025:140–145

    PubMed  CAS  Google Scholar 

  • 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 47:1117–1134

    PubMed  CAS  Google Scholar 

  • 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 303:1309–1316

    PubMed  CAS  Google Scholar 

  • Hur EM, Zhou FQ (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11:539–551

    PubMed  CAS  Google Scholar 

  • 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 206:32–37

    PubMed  CAS  Google Scholar 

  • Ichtchenko K, Hata Y, Nguyen T et al (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81:435–443

    PubMed  CAS  Google Scholar 

  • Ikeda M, Aleksic B, Kirov G et al (2010) Copy number variation in schizophrenia in the Japanese population. Biol Psychiatry 67:283–286

    PubMed  Google Scholar 

  • International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241

    Google Scholar 

  • International Schizophrenia Consortium, Purcell SM, Wray NR et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–52

    Google Scholar 

  • 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 29:300–307

    PubMed  CAS  Google Scholar 

  • Jentsch JD, Trantham-Davidson H, Jairl C et al (2009) Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology 34:2601–2608

    PubMed  CAS  Google Scholar 

  • 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 106:19593–19598

    PubMed  CAS  Google Scholar 

  • Johnstone M, Thomson PA, Hall J et al (2011) DISC1 in schizophrenia: genetic mouse models and human genomic imaging. Schizophr Bull 37:14–20

    PubMed  Google Scholar 

  • Karayiorgou M, Gogos JA (2006) Schizophrenia genetics: uncovering positional candidate genes. Eur J Hum Genet 14:512–519

    PubMed  CAS  Google Scholar 

  • 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 6:677–687

    PubMed  CAS  Google Scholar 

  • 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 69:28–34

    PubMed  CAS  Google Scholar 

  • 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 64:810–814

    PubMed  CAS  Google Scholar 

  • 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 34:1578–1589

    PubMed  CAS  Google Scholar 

  • Kato T, Kasai A, Mizuno M et al (2010) Phenotypic characterization of transgenic mice overexpressing neuregulin-1. PLoS One 5:e14185

    PubMed  Google Scholar 

  • 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 48:627–640

    PubMed  CAS  Google Scholar 

  • 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 9:925–932

    PubMed  CAS  Google Scholar 

  • 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 63:761–773

    PubMed  CAS  Google Scholar 

  • 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 83:162–176

    PubMed  CAS  Google Scholar 

  • Kirov G, Gumus D, Chen W et al (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 17:458–465

    PubMed  CAS  Google Scholar 

  • 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 18:1497–1503

    Google Scholar 

  • Kirov G, Rujescu D, Ingason A et al (2009b) Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 35:851–4

    Google Scholar 

  • 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 103:3693–3697

    PubMed  CAS  Google Scholar 

  • Knuesel I (2010) Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases. Prog Neurobiol 91:257–274

    PubMed  CAS  Google Scholar 

  • Krivoy A, Fischel T, Weizman A (2008) The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol 18:395–405

    PubMed  CAS  Google Scholar 

  • Kruzich PJ, Grandy DK (2004) Dopamine D2 receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice. BMC Neurosci 5:12

    PubMed  Google Scholar 

  • 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 105:7076–7081

    PubMed  CAS  Google Scholar 

  • 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 200:217–230

    PubMed  CAS  Google Scholar 

  • 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 34:351–372

    PubMed  CAS  Google Scholar 

  • 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 187:331–344

    PubMed  CAS  Google Scholar 

  • 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 168:302–316

    PubMed  Google Scholar 

  • 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 73:34–48

    PubMed  CAS  Google Scholar 

  • 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 35:84–89

    PubMed  CAS  Google Scholar 

  • 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 104:18280–18285

    PubMed  CAS  Google Scholar 

  • 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 29:11965–11972

    PubMed  CAS  Google Scholar 

  • 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:e12181

    PubMed  Google Scholar 

  • Lipina TV, Niwa M, Jaaro-Peled H et al (2010) Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia. Genes Brain Behav 9:777–789

    PubMed  CAS  Google Scholar 

  • Lijam N, Paylor R, McDonald MP et al (1997) Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell 90:895–905

    PubMed  CAS  Google Scholar 

  • Long JM, LaPorte P, Paylor R et al (2004) Expanded characterization of the social interaction abnormalities in mice lacking Dvl1. Genes Brain Behav 3:51–62

    PubMed  CAS  Google Scholar 

  • Long JM, LaPorte P, Merscher S et al (2006) Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics 7:247–257

    PubMed  Google Scholar 

  • 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 211:277–289

    PubMed  CAS  Google Scholar 

  • Low NC, Hardy J (2007) What is a schizophrenic mouse? Neuron 54:348–349

    PubMed  CAS  Google Scholar 

  • Maekawa M, Okamura T, Kasai N et al (2005) D-amino-acid oxidase is involved in d-serine-induced nephrotoxicity. Chem Res Toxicol 18:1678–1682

    PubMed  CAS  Google Scholar 

  • Malhotra AK, Adler CM, Kennison SD et al (1997a) Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biol Psychiatry 42:664–668

    PubMed  CAS  Google Scholar 

  • 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 13:299–310

    PubMed  CAS  Google Scholar 

  • 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 39:1045–1051

    PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM et al (1997b) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150

    PubMed  CAS  Google Scholar 

  • 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 136:1017–1031

    PubMed  CAS  Google Scholar 

  • Mathews TA, John CE, Lapa GB (2006) No role of the dopamine transporter in acute ethanol effects on striatal dopamine dynamics. Synapse 60:288–294

    PubMed  CAS  Google Scholar 

  • 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 13:299–310

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 33:1061–1079

    PubMed  CAS  Google Scholar 

  • Miller BH, Wahlestedt C (2010) MicroRNA dysregulation in psychiatric disease. Brain Res 1338:89–99

    PubMed  CAS  Google Scholar 

  • Miyamoto Y, Nabeshima T (2002) Analysis of neuronal functions in mice lacking the NMDA receptor epsilon 1 subunit. Nippon Yakurigaku Zasshi 119:327–335

    PubMed  CAS  Google Scholar 

  • Mohn AR, Gainetdinov RR, Caron MG et al (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427–436

    PubMed  CAS  Google Scholar 

  • Moore TH, Zammit S, Lingford-Hughes A (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328

    PubMed  Google Scholar 

  • Muir WJ, Pickard BS, Blackwood DH (2008) Disrupted-in-Schizophrenia-1. Curr Psychiatry Rep 10:140–147

    PubMed  Google Scholar 

  • Murotani T, Ishizuka T, Hattori S et al (2007) High dopamine turnover in the brains of Sandy mice. Neurosci Lett 421:47–51

    PubMed  CAS  Google Scholar 

  • Myin-Germeys I, Delespaul P, van Os J (2005) Behavioural sensitization to daily life stress in psychosis. Psychol Med 35:733–741

    PubMed  CAS  Google Scholar 

  • Myin-Germeys I, Oorschot M, Collip D et al (2009) Experience sampling research in psychopathology: opening the black box of daily life. Psychol Med 39:1533–1547

    PubMed  CAS  Google Scholar 

  • 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 65:480–489

    PubMed  CAS  Google Scholar 

  • Numakawa T, Yagasaki Y, Ishimoto T (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13:2699–2708

    PubMed  CAS  Google Scholar 

  • 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 177:142–149

    PubMed  CAS  Google Scholar 

  • 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 18:4576–4589

    PubMed  CAS  Google Scholar 

  • 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, Totowa

    Google Scholar 

  • 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 17:79–83

    PubMed  Google Scholar 

  • O’Tuathaigh CMP, Babovic D, O’Meara G et al (2007a) Susceptibility genes for schizophrenia: phenotypic characterisation of mutant models. Neurosci Biobehav Rev 31:60–78

    Google Scholar 

  • 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 147:18–27

    Google Scholar 

  • 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 32:462–466

    PubMed  Google Scholar 

  • O’Tuathaigh CM, Desbonnet L, Waddington JL (2009) Neuregulin-1 signalling in schizophrenia: ‘Jack of all trades’ or master of some? Expert Rev Neurother 9:1–3

    PubMed  Google Scholar 

  • O’Tuathaigh CMP, Waddington JL (2010) Mutant mouse models: phenotypic relationships to domains of psychopathology and pathobiology in schizophrenia. Schizophr Bull 36:243–245

    PubMed  Google Scholar 

  • O’Tuathaigh CMP, Kirby BP, Moran PM et al (2010a) Mutant mouse models: genotype-phenotype relationships to negative symptoms in schizophrenia. Schizophr Bull 36:271–288

    Google Scholar 

  • 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 31:349–58

    Google Scholar 

  • 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 35:2262–2273

    Google Scholar 

  • 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 67:667–673

    PubMed  CAS  Google Scholar 

  • 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 28:8709–8723

    PubMed  CAS  Google Scholar 

  • 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 17:85–98

    PubMed  CAS  Google Scholar 

  • 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 13:1102–1107

    PubMed  CAS  Google Scholar 

  • 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 103:7729–7734

    PubMed  CAS  Google Scholar 

  • 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 11:118–119

    Google Scholar 

  • 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 53:4603–4614

    PubMed  CAS  Google Scholar 

  • 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 13:173–186

    PubMed  CAS  Google Scholar 

  • 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 19:4627–4633

    PubMed  CAS  Google Scholar 

  • 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 22:9604–9611

    PubMed  CAS  Google Scholar 

  • 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 16:271–275

    PubMed  CAS  Google Scholar 

  • Rodriguiz RM, Chu R, Caron MG et al (2004) Aberrant responses in social interaction of dopamine transporter knockout mice. Behav Brain Res 148:185–198

    PubMed  CAS  Google Scholar 

  • Ross CA, Margolis RL, Reading SA et al (2006) Neurobiology of schizophrenia. Neuron 52:139–153

    PubMed  CAS  Google Scholar 

  • Rujescu D, Ingason A, Cichon S et al (2009) Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 18:988–996

    PubMed  CAS  Google Scholar 

  • Sagata N, Iwaki A, Aramaki T et al (2010) Comprehensive behavioural study of GluR4 knockout mice: implication in cognitive function. Genes Brain Behav 9:899–909

    PubMed  CAS  Google Scholar 

  • Savelieva KV, Caudle WM, Findlay GS (2002) Decreased ethanol preference and consumption in dopamine transporter female knock-out mice. Alcohol Clin Exp Res 26:758–764

    PubMed  CAS  Google Scholar 

  • Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58

    PubMed  CAS  Google Scholar 

  • Shen S, Lang B, Nakamoto C et al (2008) Schizophrenia-related neural and behavioural phenotypes in transgenic mice expressing truncated DISC1. J Neurosci 28:10893–10904

    PubMed  CAS  Google Scholar 

  • 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 44:263–277

    PubMed  CAS  Google Scholar 

  • Singer P, Boison D, Möhler H (2007) Enhanced recognition memory following glycine transporter 1 deletion in forebrain neurons. Behav Neurosci 121:815–825

    PubMed  Google Scholar 

  • 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 206:677–698

    PubMed  CAS  Google Scholar 

  • 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 21:401–413

    PubMed  CAS  Google Scholar 

  • 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 158:1393–1399

    PubMed  CAS  Google Scholar 

  • 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 40:751–760

    PubMed  CAS  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892

    PubMed  Google Scholar 

  • Steinberg S, Mors O, Børglum AD et al (2011) Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry 16:59–66

    PubMed  CAS  Google Scholar 

  • Stone JM, Morrison PD, Pilowsky LS (2007) Glutamate and dopamine dysregulation in schizophrenia-a synthesis and selective review. J Psychopharmacol 21:440–452

    PubMed  CAS  Google Scholar 

  • Szeszko PR, Hodgkinson CA, Robinson DG et al (2008) DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia. Biol Psychol 79:103–110

    PubMed  Google Scholar 

  • Takao K, Yamasaki N, Miyakawa T (2007) Impact of brain-behavior phenotyping of genetically-engineered mice on research of neuropsychiatric disorders. Neurosci Res 58:124–132

    PubMed  CAS  Google Scholar 

  • 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 1:11

    PubMed  Google Scholar 

  • 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 109:174–178

    PubMed  CAS  Google Scholar 

  • Talbot K (2009) The sandy (sdy) mouse: a dysbindin-1 mutant relevant to schizophrenia research. Prog Brain Res 179:87–94

    PubMed  CAS  Google Scholar 

  • 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 103:297–304

    PubMed  Google Scholar 

  • Tandon R, Nasrallah HA, Keshavan MS (2009) Schizophrenia, “just the facts” 4 Clinical features and conceptualization. Schizophr Res 110:1–23

    PubMed  Google Scholar 

  • 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 18:3851–3863

    PubMed  CAS  Google Scholar 

  • 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 104:205–214

    PubMed  CAS  Google Scholar 

  • Thompson BL, Levitt P (2010) The clinical-basic interface in defining pathogenesis in disorders of neurodevelopmental origin. Neuron 67:702–712

    PubMed  CAS  Google Scholar 

  • 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 101:8485–8490

    PubMed  CAS  Google Scholar 

  • Tsien JZ (2000) Linking Hebb’s coincidence-detection to memory formation. Curr Opin Neurobiol 10:266–273

    PubMed  CAS  Google Scholar 

  • Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 60:141–151

    PubMed  CAS  Google Scholar 

  • Tuominen HJ, Tiihonen J, Wahlbeck K (2005) Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res 72:225–234

    PubMed  Google Scholar 

  • 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 12:1383–1393

    PubMed  Google Scholar 

  • Van den Buuse M (2010) Modelling the positive symptoms of schizophrenia in genetically-modified mice: pharmacology and methodology aspects. Schizophr Bull 36:246–270

    PubMed  Google Scholar 

  • van Os J, Kenis G, Rutten BP (2010) The environment and schizophrenia. Nature 468:203–212

    PubMed  Google Scholar 

  • 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 181:611–638

    PubMed  CAS  Google Scholar 

  • 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 30:365–399

    Google Scholar 

  • 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 

  • Walsh T, McClellan JM, McCarthy SE et al (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543

    PubMed  CAS  Google Scholar 

  • 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 60:548–553

    PubMed  CAS  Google Scholar 

  • Wang Y, Xu R, Sasaoka T et al (2000) Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J Neurosci 20:8305–8314

    PubMed  CAS  Google Scholar 

  • Wang Q, Jaaro-Peled H, Sawa A (2008) How has DISC1 enabled drug discovery? Mol Cell Neurosci 37:187–195

    PubMed  CAS  Google Scholar 

  • 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 107:1211–1216

    PubMed  CAS  Google Scholar 

  • 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 61:544–555

    PubMed  CAS  Google Scholar 

  • Wiedholz LM, Owens WA, Horton RE et al (2008) Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors. Mol Psychiatry 13:631–640

    PubMed  CAS  Google Scholar 

  • 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 169:1511–1519

    PubMed  CAS  Google Scholar 

  • 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 7:1075–1082

    PubMed  CAS  Google Scholar 

  • Xu B, Roos JL, Levy S et al (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40:880–885

    PubMed  CAS  Google Scholar 

  • 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 106:16746–16751

    PubMed  Google Scholar 

  • 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 26:3169–3181

    PubMed  CAS  Google Scholar 

  • 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 17:145–155

    PubMed  CAS  Google Scholar 

  • 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 27:14459–14469

    PubMed  CAS  Google Scholar 

  • Zhang R, Su B (2008) MicroRNA regulation and the variability of human cortical gene expression. Nucleic Acids Res 36:4621–4628

    PubMed  CAS  Google Scholar 

  • 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 217:81–87

    PubMed  CAS  Google Scholar 

  • 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 19:3797–3805

    PubMed  CAS  Google Scholar 

  • Zhuang X, Oosting RS, Jones SR et al (2001) Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci U S A 98:1982–1987

    PubMed  CAS  Google Scholar 

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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.

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Authors and Affiliations

  1. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    Colm M. P. O’Tuathaigh, Lieve Desbonnet & John L. Waddington

  2. School of Medicine, University College Cork, Western Gateway Building, Cork, Ireland

    Colm M. P. O’Tuathaigh

  3. School of Psychology, University of Nottingham, Nottingham, NG7 2RD, UK

    Paula M. Moran

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  1. Colm M. P. O’Tuathaigh
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  2. Lieve Desbonnet
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  3. Paula M. Moran
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  4. John L. Waddington
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Correspondence to Colm M. P. O’Tuathaigh .

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  1. , Dep of Pharmacology and Therapeutics, School of Pharmacy, College Rd, Cork, 30, Ireland

    John F. Cryan

  2. , Department of Psychiatry and Psychothera, University of Würzburg, Füchsleinstrasse 15, Würzburg, 97080, Germany

    Andreas Reif

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O’Tuathaigh, C.M.P., Desbonnet, L., Moran, P.M., Waddington, J.L. (2011). Susceptibility Genes for Schizophrenia: Mutant Models, Endophenotypes and Psychobiology. In: Cryan, J., Reif, A. (eds) Behavioral Neurogenetics. Current Topics in Behavioral Neurosciences, vol 12. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2011_194

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