Advertisement

Molecular Genetic Models Related to Schizophrenia and Psychotic Illness: Heuristics and Challenges

  • Colm M. P. O’Tuathaigh
  • Lieve Desbonnet
  • Paula M. Moran
  • Brian P. Kirby
  • John L. Waddington
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 7)

Abstract

Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions.

Keywords

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

Notes

Acknowledgement

The authors’ studies are supported by a Science Foundation Ireland Principal Investigator grant (07/IN.1/B960), a Postdoctoral Fellowship from the Health Research Board (PD/2007/20), and a Wellcome Trust grant (WT 084592/Z/07/Z).

References

  1. Acevedo-Arozena A, Wells S, Potter P et al (2008) ENU mutagenesis, a way forward to understand gene function. Annu Rev Genomics Hum Genet 9:49–69PubMedGoogle Scholar
  2. 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
  3. 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
  4. Arguello PA, Gogos JA (2006) Modeling madness in mice: one piece at a time. Neuron 52:179–196PubMedGoogle Scholar
  5. Arguello PA, Gogos JA (2010) Cognition in mouse models of schizophrenia susceptibility genes. Schizophr Bull 36:289–300PubMedGoogle Scholar
  6. Asp L, Beraki S, Kristensson K et al (2009) Neonatal infection with neurotropic influenza A virus affects working memory and expression of type III Nrg1 in adult mice. Brain Behav Immun 23:733–741PubMedGoogle Scholar
  7. 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
  8. 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
  9. Bahi A, Boyer F, Kolira M et al (2005) In vivo gene silencing of CD81 by lentiviral expression of small interference RNAs suppresses cocaine-induced behaviour. J Neurochem 92:1243–1255PubMedGoogle Scholar
  10. 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
  11. Barnett JH, Scoriels L, Munafò MR (2008) Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry 64:137–144PubMedGoogle Scholar
  12. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedGoogle Scholar
  13. 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
  14. Bayer TA, Falkai P, Maier W (1999) Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the “two-hit hypothesis”. J Psychiatr Res 33:543–548PubMedGoogle Scholar
  15. 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
  16. Bertram L (2008) Genetic research in schizophrenia: new tools and future perspectives. Schizophr Bull 34:806–812PubMedGoogle Scholar
  17. Bhardwaj SK, Baharnoori M, Sharif-Askari B et al (2009) Behavioral characterization of dysbindin-deficient sandy mice. Behav Brain Res 197:435–441PubMedGoogle Scholar
  18. Blackwood DH, Fordyce A, Walker MT et al (2000) Schizophrenia and affective disorders – cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 69:428–433Google Scholar
  19. Blanchard JJ, Cohen AS (2006) The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull 32:238–245PubMedGoogle Scholar
  20. Boucher AA, Arnold JC, Duffy L et al (2007a) Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology 192:325–336PubMedGoogle Scholar
  21. 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 149:861–870PubMedGoogle Scholar
  22. Bountra C, Oppermann U, Heightman TD (2011) Animal models of epigenetic regulation in neuropsychiatric disorders. Curr Top Behav Neurosci. doi:10.1007/7854_2010_104Google Scholar
  23. Bray NJ, Preece A, Williams NM et al (2005) Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 14:1947–1954PubMedGoogle Scholar
  24. Brodkin ES, Hagemann A, Nemetski SM et al (2004) Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice. Brain Res 1002:151–157PubMedGoogle Scholar
  25. Brummelkamp TR, Bernards R, Agami R (2002) Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2:243–247PubMedGoogle Scholar
  26. Burdick KE, Goldberg TE, Funke B et al (2007) DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 89:169–172PubMedGoogle Scholar
  27. 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
  28. Callicott JH, Straub RE, Pezawas L et al (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 102:8627–8632PubMedGoogle Scholar
  29. Camargo LM, Collura V, Rain JC et al (2007) Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 12:74–86PubMedGoogle Scholar
  30. Cannon TD, Hennah W, van Erp TG et al (2005) Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 62:1205–1213PubMedGoogle Scholar
  31. 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 × environment interaction. Biol Psychiatry 57:1117–1127PubMedGoogle Scholar
  32. Chan WS et al (2011) Transgenic animal models of Huntington’s Disease. Curr Top Behav Neurosci. doi:10.1007/7854_2010_105Google Scholar
  33. Chen J, Lipska BK, Weinberger DR (2006) Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. Biol Psychiatry 59:1180–1188PubMedGoogle Scholar
  34. 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
  35. Chen XW, Feng YQ, Hao CJ et al (2008) DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. J Cell Biol 181:791–805PubMedGoogle Scholar
  36. Chubb JE, Bradshaw NJ, Soares DC (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64PubMedGoogle Scholar
  37. Clapcote SJ, Lipina TV, Millar JK et al (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402PubMedGoogle Scholar
  38. Clifford JJ, Kinsella A, Tighe O et al (2001) Comparative, topographically-based evaluation of behavioural phenotype and specification of D(1)-like:D(2) interactions in a line of incipient congenic mice with D(2) dopamine receptor ‘knockout’. Neuropsychopharmacology 25:527–536PubMedGoogle Scholar
  39. Cordes SP (2005) N-ethyl-N-nitrosourea mutagenesis: boarding the mouse mutant express. Microbiol Mol Biol Rev 69:426–439PubMedGoogle Scholar
  40. Corvin A, Donohoe G, Nangle JM et al (2008) A dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis. Neurosci Lett 431:146–149PubMedGoogle Scholar
  41. 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
  42. Cox MM, Tucker AM, Tang J et al (2009) Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background. Genes Brain Behav 8:390–397PubMedGoogle Scholar
  43. Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384PubMedGoogle Scholar
  44. Crusio WE (2004) Flanking gene and genetic background problems in genetically manipulated mice. Biol Psychiatry 56:381–385PubMedGoogle Scholar
  45. Crusio WE, Goldowitz D, Holmes A et al (2009) Standards for the publication of mouse mutant studies. Genes Brain Behav 8:1–4PubMedGoogle Scholar
  46. Dean B, Karl T, Pavey G et al (2008) Increased levels of serotonin 2S receptors and serotonin transporter in the CNS of neuregulin 1 hypomorphic/mutant mice. Schizophr Res 99:341–349PubMedGoogle Scholar
  47. Desbonnet L, Waddington JL, O’Tuathaigh CM (2009a) Mice mutant for genes associated with schizophrenia: common phenotype or distinct endophenotypes? Behav Brain Res 204:258–273PubMedGoogle Scholar
  48. Desbonnet L, Waddington JL, O’Tuathaigh CM (2009b) Mutant models for genes associated with schizophrenia. Biochem Soc Trans 37:308–312PubMedGoogle Scholar
  49. DeSteno DA, Schmauss C (2009) A role for dopamine D2 receptors in reversal learning. Neuroscience 162:118–127Google Scholar
  50. Di Giorgio A, Blasi G, Sambataro F et al (2008) Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding. Eur J Neurosci 28:2129–2136PubMedGoogle Scholar
  51. Dinan TG (2009) MicroRNAs as a target for novel antipsychotics: a systematic review of an emerging field. Int J Neuropsychopharmacol 23:1–10Google Scholar
  52. Donohoe G, Morris DW, Clarke S et al (2007) Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study. Neuropsychologia 45:454–458PubMedGoogle Scholar
  53. Donohoe G, Morris DW, De Sanctis P et al (2008) Early visual processing deficits in dysbindin-associated schizophrenia. Biol Psychiatry 63:484–489PubMedGoogle Scholar
  54. 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
  55. 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
  56. Duncan GE, Moy SS, Perez A et al (2004) Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507–519PubMedGoogle Scholar
  57. 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
  58. Eells B, Misler JA, Nikodem V (2006) Reduced tyrosine hydroxylase and GTP cyclohydrolase mRNA expression, tyrosine hydroxylase activity, and associated neurochemical alterations in Nurr1-null heterozygous mice. Brain Res Bull 70:186–195PubMedGoogle Scholar
  59. Ehrlichman RS, Luminais SN, White SL et al (2009) Neuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions. Brain Res 1294:116–127PubMedGoogle Scholar
  60. 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
  61. 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
  62. Fallgatter AJ, Hermann MJ, Hohoff C et al (2006) DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals. Neuropsychopharmacology 31:2000–2010Google Scholar
  63. Fanous AH, Neale MC, Straub RE et al (2004) Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet B Neuropsychiatr Genet 125B:69–78PubMedGoogle Scholar
  64. 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
  65. File SE (1980) The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods 2:219–238PubMedGoogle Scholar
  66. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114PubMedGoogle Scholar
  67. Freedman R, Olincy A, Buchanan RW et al (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165:1040–1047PubMedGoogle Scholar
  68. Fremeau RT Jr, Troyer MD, Pahner I et al (2001) The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31:247–260PubMedGoogle Scholar
  69. Gainetdinov RR (2008) Dopamine transporter mutant mice in experimental neuropharmacology. Naunyn Schmiedebergs Arch Pharmacol 377:301–313PubMedGoogle Scholar
  70. Garcia-Garcia AL, Elizalde N, Matrov D et al (2009) Increased vulnerability to depressive-like behaviour of mice with decreased expression of VGLUT1. Biol Psychiatry 66:275–282PubMedGoogle Scholar
  71. Gerlai R, Clayton NS (1999) Analysing hippocampal function in transgenic mice: an ethological perspective. Trends Neurosci 22:46–51Google Scholar
  72. Gerlai R, Pisacane P, Erickson S (2000) Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks. Behav Brain Res 109:219–227PubMedGoogle Scholar
  73. Gill M, Donohoe G, Corvin A (2009) What have the genomics ever done for the psychoses? Psychol Med 12:1–12Google Scholar
  74. 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
  75. Gogos JA (2007) Schizophrenia susceptibility genes: in search of a molecular logic and novel drug targets for a devastating disorder. Int Rev Neurobiol 78:397–422PubMedGoogle Scholar
  76. 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
  77. Gogos JA, Santha M, Takacs Z (1999) The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat Genet 21:434–439PubMedGoogle Scholar
  78. Gondo Y (2008) Trends in large-scale mouse mutagenesis: from genetics to functional genomics. Nat Rev Genet 9:803–810PubMedGoogle Scholar
  79. Gondo Y, Murata T, Makino S, Fukumura R, Ishitsuka Y (2011) Mouse mutagenesis and disease models for neuropsychiatric disorders. Curr Top Behav Neurosci. doi:10.1007/7854_2010_106Google Scholar
  80. Gong YG, Wu CN, Xing QH et al (2009) A two-method meta-analysis of neuregulin 1 (NRG1) association and heterogeneity in schizophrenia. Schizophr Res 111:109–114PubMedGoogle Scholar
  81. Guillin O, Abi-Dargham A, Laruelle M (2007) Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 78:1–39PubMedGoogle Scholar
  82. 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
  83. 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
  84. Halene TB, Amann LC, Ehrlichman RS et al (2009) Neurobehavioral abnormalities in dysbindin-1 mutant mice on a C57BL/6J background. (Presentation at 2009 Society for Neuroscience Annual Meeting, Chicago, IL).Google Scholar
  85. Harrison PJ, Law AJ (2006) Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 60:132–140PubMedGoogle Scholar
  86. 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
  87. 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
  88. Henquet C, Rosa A, Krabbendam L et al (2006) An experimental study of catechol-O-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 31:2748–2757PubMedGoogle Scholar
  89. 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
  90. Hoffmann I, Bueter W, Zscheppang K et al (2010) Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns. Behav Brain Immun 24:784–791Google Scholar
  91. 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
  92. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull 35:549–562PubMedGoogle Scholar
  93. 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
  94. Ichtchenko K, Hata Y, Nguyen T et al (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81:435–443PubMedGoogle Scholar
  95. Ikeda M, Aleksic B, Kirov G et al (2010) Copy number variation in schizophrenia in the Japanese population. Biol Psychiatry 67:283–286PubMedGoogle Scholar
  96. International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241Google Scholar
  97. International Schizophrenia Consortium, Purcell SM, Wray NR et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–752PubMedGoogle Scholar
  98. Jaaro-Peled H, Ayhan Y, Pletnikov MV et al (2010) Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models. Schizophr Bull 36:480–489Google Scholar
  99. 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
  100. Karasinska JM, George SR, Cheng R et al (2005) Deletion of dopamine D1 and D3 receptors differentially affects spontaneous behaviour and cocaine-induced locomotor activity, reward, and CREB phosphorylation. Eur J Neurosci 22:1741–1750PubMedGoogle Scholar
  101. Karayiorgou M, Gogos JA (2006) Schizophrenia genetics: uncovering positional candidate genes. Eur J Hum Genet 14:512–519PubMedGoogle Scholar
  102. 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
  103. 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
  104. 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
  105. 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
  106. Kellendonk C, Simpson EH, Kandel ER (2009) Modeling cognitive endophenotypes of schizophrenia in mice. Trends Neurosci 32:347–358PubMedGoogle Scholar
  107. Kelly BD, O’Callaghan E, Waddington JL et al (2010) Schizophrenia and the city: a review of literature and prospective study of psychosis and urbanicity in Ireland. Schizophr Res 116:75–89PubMedGoogle Scholar
  108. 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
  109. Kirkbride J, Boydell J, Ploubidis GB et al (2008) Testing the association between the incidence of schizophrenia and social capital in an urban area. Psychol Med 38:1083–1094PubMedGoogle Scholar
  110. 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
  111. 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 18:1497–1503PubMedGoogle Scholar
  112. Kirov G, Rujescu D, Ingason A et al (2009b) Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 35:851–854PubMedGoogle Scholar
  113. Kocerha J, Faghihi MA, Lopez-Toledano MA et al (2009) MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA 106:3507–3512PubMedGoogle Scholar
  114. 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
  115. Kruzich PJ, Grandy DK (2004) Dopamine D2 receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice. BMC Neurosci 5:12PubMedGoogle Scholar
  116. 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
  117. 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
  118. Law AJ, Kleinman JE, Weinberger DR et al (2007) Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum Mol Genet 16:129–141PubMedGoogle Scholar
  119. Le Strat Y, Ramoz N, Gorwood P (2009) The role of genes involved in neuroplasticity and neurogenesis in the observation of a gene–environment interaction (G×E) in schizophrenia. Curr Mol Med 9:506–518PubMedGoogle Scholar
  120. Lencz T, Lambert C, De Rosse P et al (2007) Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. Proc Natl Acad Sci USA 104:19942–19947PubMedGoogle Scholar
  121. Lesch KP (2011) When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. Curr Top Behav Neurosci. doi:10.1007/7854_2010_109Google Scholar
  122. Li D, He L (2006) Association study of the G-protein signalling 4 (RGS4) and proline dehydrogenase (PRODH) genes with schizophrenia: a meta-analysis. Eur J Hum Genet 14:1130–1135PubMedGoogle Scholar
  123. 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
  124. 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
  125. Liu H, Heath SC, Sobin C et al (2002) Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 99:3717–3722PubMedGoogle Scholar
  126. Liu YL, Fann CS, Liu CM et al (2007) HTF9C gene of 22q11.21 region associates with schizophrenia having deficit-sustained attention. Psychiatr Genet 17:333–338PubMedGoogle Scholar
  127. Low NC, Hardy J (2007) What is a schizophrenic mouse? Neuron 54:348–349PubMedGoogle Scholar
  128. Mahairaki V, Xu L, Farah MH et al (2009) Targeted knock-down of neuronal nitric oxide synthase expression in basal forebrain with RNA interference. J Neurosci Methods 179:292–299PubMedGoogle Scholar
  129. Malhotra AK, Adler CM, Kennison SD et al (1997) Clozapine blunts N-methyl-d-aspartate antagonist-induced psychosis: a study with ketamine. Biol Psychiatry 42:664–668PubMedGoogle Scholar
  130. Markov V, Krug A, Krach S et al (2009) Genetic variation in schizophrenia-risk-gene dysbindin 1 modulates brain activation in anterior cingulate cortex and right temporal gyrus during language production in healthy individuals. Neuroimage 47:2016–2022PubMedGoogle Scholar
  131. McGrath J, Saha S, Chant D et al (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30:67–76PubMedGoogle Scholar
  132. McNamara FN, Clifford JJ, Tighe O et al (2002) Phenotypic, ethologically based resolution of spontaneous and D(2)-like vs D(1)-like agonist-induced behavioural topography in mice with congenic D(3) dopamine receptor “knockout”. Synapse 46:19–31PubMedGoogle Scholar
  133. Meechan DW, Maynard TM, Gopalakrishna D et al (2007) When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. Gene Expr 13:299–310PubMedGoogle Scholar
  134. Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9:437–452PubMedGoogle Scholar
  135. Meyer U, Nyffeler M, Yee BK et al (2008) Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 22:469–486PubMedGoogle Scholar
  136. 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
  137. Miyamoto Y, Yamada K, Noda Y et al (2001) Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor epsilon1 subunit. J Neurosci 21:750–757PubMedGoogle Scholar
  138. 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
  139. Moser PC, Hitchcock JM, Lister S et al (2000) The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Rev 33:275–307PubMedGoogle Scholar
  140. Moskvina V, Craddock N, Holmans P et al (2009) Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 14:252–260PubMedGoogle Scholar
  141. Moy SS, Perez A, Koller BH et al (2006) Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function. Brain Res 1089:186–194PubMedGoogle Scholar
  142. Mukai J, Liu H, Burt RA et al (2004) Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet 36:725–731PubMedGoogle Scholar
  143. Mukai J, Dhilla A, Drew LJ et al (2008) Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci 11:1302–1310PubMedGoogle Scholar
  144. Murphy KC, Owen MJ (2001) Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia. Br J Psychiatry 179:397–402PubMedGoogle Scholar
  145. Murphy KC, Jones LA, Owen MJ (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 56:940–945PubMedGoogle Scholar
  146. Nielsen TT, Marion I, Hasholt L et al (2009) Neuron-specific RNA interference using lentiviral vectors. J Gene Med 11:559–569PubMedGoogle Scholar
  147. Nolan PM, Peters J, Strivens M et al (2000) A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat Genet 25:440–443PubMedGoogle Scholar
  148. O’Sullivan GJ, O’Tuathaigh CM, Clifford JJ et al (2006) Potential and limitations of genetic manipulation in animals. Drug Discov Today: Technologies 3:173–180Google Scholar
  149. 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
  150. 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
  151. O’Tuathaigh CMP, Babovic D, O’Meara G et al (2007a) Susceptibility genes for schizophrenia: phenotypic characterisation of mutant models. Neurosci Biobehav Rev 31:60–78PubMedGoogle Scholar
  152. 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 147:18–27PubMedGoogle Scholar
  153. 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
  154. O’Tuathaigh CM, Desbonnet L, Waddington JL (2009a) Neuregulin-1 signalling in schizophrenia: ‘Jack of all trades’ or master of some? Expert Rev Neurother 9:1–3PubMedGoogle Scholar
  155. O’Tuathaigh CM, Hryniewiecka M, Behan A et al (2009b) Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT knockout mice: Impact on phenotypes relevant to psychosis. Program No. 248.9. Abstract Viewer/Itinerary Planner. Society for Neuroscience, Chicago, ILGoogle Scholar
  156. O’Tuathaigh CMP, Kirby BP, Moran PM et al (2010a) Mutant mouse models: genotype–phenotype relationships to negative symptoms in schizophrenia. Schizophr Bull 36:271–288PubMedGoogle Scholar
  157. 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 31:349–358PubMedGoogle Scholar
  158. 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
  159. Oni-Orisan A, Kristiansen LV, Haroutunian V et al (2008) Altered vesicular glutamate transporter expression in the anterior cingulate cortex in schizophrenia. Biol Psychiatry 63:766–775PubMedGoogle Scholar
  160. Panksepp J (2006) Emotional endophenotypes in evolutionary psychiatry. Prog Neuropsychopharmacol Biol Psychiatry 30:774–784PubMedGoogle Scholar
  161. 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
  162. Paterlini M, Zakharenko SS, Lai WS et al (2005) Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci 8:1586–1594PubMedGoogle Scholar
  163. 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
  164. Perkins DO, Jeffries CD, Jarskog LF et al (2007) microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 8:R27PubMedGoogle Scholar
  165. 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
  166. 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
  167. Powell SB, Geyer MA (2007) Overview of animal models of schizophrenia. Curr Protoc Neurosci 9:9.24Google Scholar
  168. Powell CM, Miyakawa T (2006) Schizophrenia-relevant behavioral testing in rodent models: a uniquely human disorder? Biol Psychiatry 59:1198–1207PubMedGoogle Scholar
  169. Prasad SE, Howley S, Murphy KC (2008) Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. Dev Disabil Res Rev 14:26–34PubMedGoogle Scholar
  170. 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
  171. 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
  172. 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
  173. 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
  174. Roy K, Murtie JC, El-Khodor BF et al (2007) Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci USA 104:8131–8136PubMedGoogle Scholar
  175. 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
  176. Sammut S, Goodall G, Muscat R (2001) Acute interferon-alpha administration modulates sucrose consumption in the rat. Psychoneuroendocrinology 26:261–272PubMedGoogle Scholar
  177. Sauer B (1993) Manipulation of transgenes by site-specific recombination: use of Cre recombinase. Methods Enzymol 225:890–900PubMedGoogle Scholar
  178. Savonenko AV, Melnikova T, Laird FM et al (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci USA 105:5585–5590PubMedGoogle Scholar
  179. Schumacher J, Laje G, Abou Jamra R et al (2009) The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations. Hum Mol Genet 18:2719–2727PubMedGoogle Scholar
  180. Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58PubMedGoogle Scholar
  181. Selten JP, Cantor-Graae E (2007) Hypothesis: social defeat is a risk factor for schizophrenia? Br J Psychiatry 51(Suppl):s9–s12Google Scholar
  182. 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
  183. Shi J, Gershon ES, Liu C (2008) Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. Schizophr Res 104:96–107PubMedGoogle Scholar
  184. Shifman S, Johannesson M, Bronstein M et al (2008) Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 4:e28PubMedGoogle Scholar
  185. Singer O, Verma IM (2008) Applications of lentiviral vectors for shRNA delivery and transgenesis. Curr Gene Ther 8:483–488PubMedGoogle Scholar
  186. 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
  187. 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
  188. Stefansson H, Sigurdsson E, Steinthorsdottir V et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892PubMedGoogle Scholar
  189. Stone JM, Morrison PD, Pilowsky LS (2007) Glutamate and dopamine dysregulation in schizophrenia – a synthesis and selective review. J Psychopharmacol 21:440–452PubMedGoogle Scholar
  190. 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 1:11Google Scholar
  191. 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
  192. Talbot K, Cho DS, Ong WY et al (2006) Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Hum Mol Genet 15:3041–3054PubMedGoogle Scholar
  193. Taliaz D, Stall N, Dar DE et al (2010) Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 15:80–92PubMedGoogle Scholar
  194. Tandon R, Keshavan MS, Nasrallah HA (2008) Schizophrenia, “just the facts”: what we know in 2008 part 1: overview. Schizophr Res 100:4–19PubMedGoogle Scholar
  195. Thimm M, Krug A, Markov V et al (2010) The impact of dystrobrevin-binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval. Hum Brain Mapp 31:203–209PubMedGoogle Scholar
  196. Tillerson JL, Caudle WM, Parent JM et al (2006) Olfactory discrimination deficits in mice lacking the dopamine transporter or D2 dopamine receptor. Behav Brain Res 172:97–105PubMedGoogle Scholar
  197. Tiscornia G, Singer O, Ikawa M et al (2003) A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 100:1844–1848PubMedGoogle Scholar
  198. Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 60:141–151PubMedGoogle Scholar
  199. 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
  200. Van OS J, Kapur S (2009) Schizophrenia. Lancet 374:635–645PubMedGoogle Scholar
  201. 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
  202. Waddington JL, Corvin AP, Donohoe G, O’Tuathaigh CMP, Mitchell KJ, Gill M (2007) Functional genomics and schizophrenia: endophenotypes and mutant models. Psychiatr Clin N Am 30:365–399Google Scholar
  203. Wallén-Mackenzie A, Nordenankar K, Fejgin K et al (2009) Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function. J Neurosci 29:2238–2251PubMedGoogle Scholar
  204. 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
  205. 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
  206. 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
  207. Weiner I, Arad M (2009) Using the pharmacology of latent inhibition to model domains of pathology in schizophrenia and their treatment. Behav Brain Res 204:369–386PubMedGoogle Scholar
  208. Welham J, Isohanni M, Jones P et al (2009) The antecedents of schizophrenia: a review of birth cohort studies. Schizophr Bull 35:603–623PubMedGoogle Scholar
  209. Williams HJ, Owen MJ, O’Donovan MC (2009) Schizophrenia genetics: new insights from new approaches. Br Med Bull 91:61–74PubMedGoogle Scholar
  210. Winograd-Gurvich C, Fitzgerald PB, Georgiou-Karistianis N et al (2006) Negative symptoms: a review of schizophrenia, melancholic depression and Parkinson’s disease. Brain Res Bull 70:312–321PubMedGoogle Scholar
  211. 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
  212. Yamauchi Y, Qin LH, Nishihara M et al (2005) Vulnerability of synaptic plasticity in the complexin II knockout mouse to maternal deprivation stress. Brain Res 1056:59–67PubMedGoogle Scholar
  213. 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
  214. Zamore PD (2001) RNA interference: listening to the sound of silence. Nat Struct Biol 8:746–750PubMedGoogle Scholar
  215. Zhang R, Su B (2008) MicroRNA regulation and the variability of human cortical gene expression. Nucleic Acids Res 36:4621–4628PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Colm M. P. O’Tuathaigh
    • 1
  • Lieve Desbonnet
    • 1
  • Paula M. Moran
    • 2
  • Brian P. Kirby
    • 3
  • John L. Waddington
    • 1
  1. 1.Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublin 2Ireland
  2. 2.School of PsychologyUniversity of NottinghamNottinghamUK
  3. 3.School of PharmacyRoyal College of Surgeons in IrelandDublinIreland

Personalised recommendations