Mutant mouse models: Genotype-phenotype relationships to negative symptoms in schizophrenia

Schizophrenia Bulletin

Volumn 36, Issue 2, 2010, Pages 271-288

  O'Tuathaigh, Colm M P ^a   Kirby, Brian P ^a   Moran, Paula M ^b   Waddington, John L ^a  

^a ROYAL COLLEGE OF SURGEONS IN IRELAND   (Ireland)

^b UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

Anhedonia; Avolition; Pathobiology; Psychopathology; Psychosis; Social behavior

Indexed keywords

ANTIDEPRESSANT AGENT; ARGIPRESSIN; CATECHOL METHYLTRANSFERASE; CLOZAPINE; DOPAMINE; DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE 4 RECEPTOR; DOPAMINE 5 RECEPTOR; DOPAMINE TRANSPORTER; DYSBINDIN; EXCITATORY AMINO ACID TRANSPORTER; GLUTAMATE RECEPTOR; HALOPERIDOL; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR 5; N METHYL DEXTRO ASPARTIC ACID; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 1; NEU DIFFERENTIATION FACTOR; NEUROLEPTIC AGENT; OXYTOCIN; REELIN; RGS4 PROTEIN; SYNAPSIN II; VESICULAR GLUTAMATE TRANSPORTER 1; VESICULAR GLUTAMATE TRANSPORTER 2;

AGGRESSION; ANHEDONIA; AVOLITION; BIPOLAR DISORDER; BIPOLAR MANIA; BLUNTED AFFECT; CHAKRAGATI MOUSE; CHROMOSOME TRANSLOCATION; COGNITIVE DEFECT; DOPAMINERGIC TRANSMISSION; EMOTION; EXPERIMENTAL MODEL; GENE DELETION; GENETIC ASSOCIATION; GENETIC RISK; GENOTYPE; HUMAN; MOUSE STRAIN; NEGATIVE SYNDROME; NEUROBIOLOGY; NONHUMAN; PATHOLOGY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PSYCHOSOCIAL WITHDRAWAL; REVIEW; SCHIZOPHRENIA; SOCIAL AVOIDANCE BEHAVIOR; SOCIAL BEHAVIOR; SOCIAL DISCRIMINATION; SOCIAL DOMINANCE;

AFFECTIVE SYMPTOMS; ANIMALS; BRAIN; DISEASE MODELS, ANIMAL; DNA MUTATIONAL ANALYSIS; DOPAMINE; GENETIC ASSOCIATION STUDIES; GENOTYPE; GLUTAMIC ACID; HUMANS; MICE; MICE, MUTANT STRAINS; MOTIVATION; PHENOTYPE; SCHIZOPHRENIA; SCHIZOPHRENIC PSYCHOLOGY; SOCIAL BEHAVIOR;

EID: 77749291919     PISSN: 05867614     EISSN: 17451701     Source Type: Journal    
DOI: 10.1093/schbul/sbp125     Document Type: Review

References (204)

1. Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32:214-219.
2. Stahl SM, Buckley PF. Negative symptoms of schizophrenia: a problem that will not go away. Acta Psychiatr Scand. 2007;115:4-11.
3. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia "just the facts" 4. Clinical features and conceptualization. Schizophr Res. 2009;110:1-23.
4. Ellenbroek BA, Cools AR. Animal models for the negative symptoms of schizophrenia. Behav Pharmacol. 2000;11: 223-233.
5. Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuro-psychopharmacology. 2000;23:223-239.
6. Murphy BP, Chung YC, Park TW, McGorry PD. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res. 2006;88:5-25.
7. Blanchard JJ, Cohen AS. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull. 2006;32:238-245.
8. Harvey PD, Koren D, Reichenberg A, Bowie CR. Negative symptoms and cognitive deficits: what is the nature of their relationship? Schizophr Bull. 2006;32:250-258.
9. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in Schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474-1486.
10. Guillin O, Abi-Dargham A, Laruelle M. Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol. 2007;78:1-39.
11. Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry. 2008;165:1015-1023.
12. Stephan KE, Baldeweg T, Friston KJ. Synaptic plasticity and disconnection in schizophrenia. Biol Psychiatry. 2006;59:929-939.
13. Winograd-Gurvich C, Fitzgerald PB, Georgiou-Karistianis N, Bradshaw JL, White OB. Negative symptoms: a review of schizophrenia, melancholic depression and Parkinson's disease. Brain Res Bull. 2006;70:312-321.
14. Whitty PF, Owoeye O, Waddington JL. Neurological signs and involuntary movements in schizophrenia: intrinsic to and informative on systems pathobiology. Schizophr Bull. 2009;35:415-424.
15. Low NC, Hardy J. What is a schizophrenic mouse? Neuron. 2007;54:348-349.
16. Powell CM, Miyakawa T. Schizophrenia-relevant behavioral testing in rodent models: a uniquely human disorder? Biol Psychiatry. 2006;59:1198-1207.
17. Panksepp J. Emotional endophenotypes in evolutionary psychiatry. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:774-784.
18. O'Tuathaigh CMP, Babovic D, O'Meara G, Clifford JJ, Croke DT, Waddington JL. Susceptibility genes for schizophrenia: phenotypic characterisation of mutant models. Neurosci Biobehav Rev. 2007;31:60-78.
19. Arguello PA, Gogos JA. Modeling madness in mice: one piece at a time. Neuron. 2006;52:179-196.
20. File SE. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods. 1980;2:219-238.
21. Sams-Dodd F. Automation of the social interaction test by a video-tracking system: behavioural effects of repeated phencyclidine treatment. J Neurosci Methods. 1995;59: 157-167.
22. File SE, Seth P. A review of 25 years of the social interaction test. Eur J Pharmacol. 2003;463:35-53
23. Futamura T, Kakita A, Tohmi M, Sotoyama H, Takahashi H, Nawa H. Neonatal perturbation of neurotrophic signalling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development. Mol Psychiatry. 2003;8:19-29.
24. SankoorikalGK, KaercherKA, Boon CJ, Lee JK, BrodkinES. A mouse model system for genetic analysis of sociability: C57BL/6J vs. BALB/cJ inbred mouse strains. Biol Psychiatry. 2006;59:415-423.
25. Moy SS, Nadler JJ, Young NB, et al. Social approach and repetitive behaviour in eleven inbred mouse strains. Behav Brain Res. 2008;191:118-129.
26. Brodkin ES, Hagemann A, Nemetski SM, Silver LM. Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice. Brain Res. 2004;1002:151-157.
27. Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 2004;3:287-302.
28. Couture SM, Penn DL, Roberts DL. The functional significance of social cognition in schizophrenia: a review. Schizophr Bull. 2006;32:S44-S63.
29. Perio A, Terranova JP, Worms P, et al. Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psy-chostimulants. Psychopharmacology. 1989;97:262-268.
30. Depoortere R, Auclair AL, Bardin L, et al. F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms. Br J Pharmacol. 2007;151:266-277.
31. Barkataki I, Kumari V, Das M, et al. A neuropsychological investigation into violence and mental illness. Schizophr Res. 2005;74:1-13.
32. Song H, Min SK. Aggressive behaviour model in schizophrenic patients. Psychiatry Res. 2009;167:58-65.
33. Blanchard RJ, Wall PM, Blanchard DC. Problems in the study of rodent aggression. Horm Behav. 2003;44:161-170
34. Rawleigh JM, Kemble ED. Test-specific effects of FG-7142 on isolation-induced aggression in mice. Pharmacol Biochem Behav. 1992;42:317-321.
35. Miczek KA, Maxson SC, Fish EW, Faccidomo S. Aggressive behavioural phenotypes in mice. Behav Brain Res. 2001;125:167-181.
36. Roubertoux PL, Guillot PV, Mortaud S, et al. Attack behaviors in mice: from factorial structure to quantitative trait loci mapping. Eur J Pharmacol. 2005;526:172-185.
37. Ogawa S, Choleris E, Pfaff D. Genetic influences on aggressive behaviors and arousability in animals. Ann N Y Acad Sci. 2004;1036:257-266.
38. Selten JP, Cantor-Graae E. Social defeat: risk factor for schizophrenia? Br J Psychiatry. 2005;187:101-102.
39. Price JS. Social defeat and schizophrenia. Br J Psychiatry. 2006;188:393.
40. Lathe R. The individuality of mice. Genes Brain Behav. 2004;3:317-327.
41. Lijam N, Paylor R, McDonald MP, et al. Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell. 1997;90:895-905.
42. Daenen EW, Wolterink G, Gerrits MA, Van Ree JM. The effects of neonatal lesions in the amygdala or ventral hippocampus on social behaviour in later life. Behav Brain Res. 2002;136:571-582.
43. Terranova ML, Laviola G. Delta-opioid modulation of social interactions in juvenile mice weaned at different ages. Physiol Behav. 2001;73:393-400.
44. Lim MA, Stack CM, Cuasay K, et al. Regardless of genotype, offspring of VIP-deficient female mice exhibit developmental delays and deficits in social behaviour. Int J Dev Neurosci. 2008;26:423-434.
45. Willner P, Muscat R, Papp M. An animal model of anhedo-nia. Clin Neuropharmacol. 1992;15:550A-551A.
46. Sammut S, Goodall G, Muscat R. Acute interferon-alpha administration modulates sucrose consumption in the rat. Psychoneuroendocrinology. 2001;26:261-272.
47. Baird JP, Turgeon S, Wallman A, Hulick V. Behavioral processes mediating phencyclidine-induced decreases in voluntary sucrose consumption. Pharmacol Biochem Behav. 2008;88:272-279.
48. Zurita A, Murua S, Molina V. An endogenous opiate mechanism seems to be involved in stress-induced anhedonia. Eur J Pharmacol. 1996;299:1-7.
49. Zurita A, Martijena I, Cuadra G, Brandao ML, Molina V. Early exposure to chronic variable stress facilitates the occurrence of anhedonia and enhanced emotional reactions to novel stressors: reversal by naltrexone pretreatment. Behav Brain Res. 2000;117:163-171.
50. Cilia J, Piper DC, Upton N, Hagan JJ. Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule. Psychopharmacology. 2001;155:135-143.
51. Schwabe K, Klein S, Koch M. Behavioural effects of neonatal lesions of the medial prefrontal cortex and subchronic pubertal treatment with phencyclidine of adult rats. Behav Brain Res. 2006;168:150-160
52. DieckmannM, Freudenberg F, KleinS, KochM, Schwabe K. Disturbed social behaviour and motivation in rats selectively bred for deficient sensorimotor gating. Schizophr Res. 2007;97:250-253.
53. Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K. Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology. 1991;104:515-521.
54. Sokoloff P. Focusonclozapine: a new explanation for its atypical character. Int J Neuropsychopharmacol. 2005;8:311-313.
55. Wallen-Mackenzie A, Nordenankar K, Fejgin K, et al. Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopa-minergic activity and neuronal circuitry of higher brain function. J Neurosci. 2009;29:2238-2251.
56. Joffe G, Venalainen E, Tupala J, et al. The effect of cloza-pine on the course of illness in chronic schizophrenia: focus on treatment outcome in out-patients. Int Clin Neuropsycho-pharmacol. 1996;11:265-272.
57. Rueter LE, Ballard ME, Gallagher KB, Basso AM, Curzon P, Kohlhaas KL. Chronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia. Psycho-pharmacology. 2004;176:312-319.
58. Murray RM, Lappin J, Di Forti M. Schizophrenia: from developmental deviance to dopaminergic dysregulation. Eur Neuropsychopharmacol. 2008;18:S129-S34.
59. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull. 2009;35:549-562.
60. Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40: 827-834.
61. Hwang R, Shinkai T, De Luca V, et al. Association study of four dopamine D1 receptor gene polymorphisms and cloza-pine treatment response. J Psychopharmacol. 2007;21:718-727.
62. Bertolino A, Fazio L, Caforio G, et al. Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain. 2009;132: 417-425.
63. Lane HY, Lee CC, Chang YC, Lu CT, Huang CH, Chang WH. Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function. Int J Neuropsychopharma-col. 2004;7:461-470.
64. Waddington JL, O'Tuathaigh C, O'Sullivan G, Tomiyama K, Koshikawa N, Croke DT. Phenotypic studies on dopa-mine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology-molecular biology interface. Psycho-pharmacology. 2005;181:611-638.
65. O'Sullivan GJ, O'Tuathaigh C, Tomiyama K, Koshikawa N, Waddington JL. Dopamine receptors and behavior: from psychopharmacology to mutant models. In: Neve K, ed. The Dopamine Receptors. Totawa, NJ: Humana Press, 2nd ed. In press.
66. Hranilovic D, Bucan M, Wang YY. Emotional response in dopamine D2L receptor-deficient mice. Behav Brain Res. 2008;195:246-250.
67. Elmer GI, Pieper JO, Levy J, et al. Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice. Psychopharmacology. 2005;182:33-44.
68. Drew MR, Simpson EH, Kellendonk C, et al. Transient over-expression of striatal D2 receptors impairs operant motivationandintervaltiming. JNeurosci. 2007;27:7731-7739.
69. Fanous AH, Neale MC, Straub RE, et al. Clinical features of psychotic disorders and polymorphisms in 5HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet B Neuropsychiatr Genet. 2004;125B:69-78.
70. Gainetdinov RR. Dopamine transporter mutant mice in experimental neuropharmacology. Naunyn-Schmiedeberg's Arch Pharmacol. 2008;377:301-313.
71. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996;379:606-612.
72. Rodriguiz RM, Chu R, Caron MG, Wetsel WC. Aberrant responses in social interaction of dopamine transporter knockout mice. Behav Brain Res. 2004;148:185-198.
73. Tillerson JL, Caudle WM, Parent JM, Gong C, Schallert T, Miller GW. Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor 2006. Behav Brain Res. 2006;172:97-105.
74. Costa RM, Gutierrez R, de Araujo IE, et al. Dopamine levels modulate the updating of tastant values. Genes Brain Behav. 2007;6:314-320.
75. Hironaka N, Ikeda K, Sora I, Uhl GR, Nikki H. Food-reinforced operant behavior in dopamine transporter knockout mice\enhanced resistance to extinction. Ann N Y Acad Sci. 2004;1025:140-145.
76. Perona MTG, Waters S, Hall FS, et al. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. Behav Pharmacol. 2008;19:566-574.
77. Cagniard B, Balsam PD, Brunner D, Zhuang XX. Mice with chronically elevated dopamine exhibit enhanced motivation, but not learning, for a food reward. Neuropsychopharmacology. 2006;31:1362-1370.
78. Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry. 2006;60:141-151.
79. Williams HJ, Owen MJ, O'Donovan MC. Is COMT a susceptibility gene for schizophrenia? Schizophr Bull. 2007;33:635-641.
80. Barnett JH, Scoriels L, Munafò MR. Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry. 2008;64: 137-144.
81. Zammit S, Jones G, Jones SJ, et al. Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;128:19-20.
82. Kim YR, Kim JH, Kim SJ, Lee D, Min SK. Catechol-O-methyltransferase Val158Met polymorphism in relation to aggressive schizophrenia in a Korean population. Eur Neuropsychopharmacol. 2008;18:820-825.
83. Babovic D, O'Tuathaigh CM, O'Connor AM, et al. Pheno-typic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of cate-chol-O-methyltransferase. Neuroscience. 2008;155:1021-1029.
84. Gogos JA, Morgan M, Luine V, et al. Catechol-O-methyl-transferase- deficient mice exhibit sexually dimorphic changes in catecholamine levels and behaviour. Proc Natl Acad Sci USA. 1998;95:9991-9996.
85. Torres G, Meeder BA, Hallas BH, Gross KW, Horowitz JM. Preliminary evidence for reduced social interactions in Chak-ragati mutants modelling certain symptoms of schizophrenia. Brain Res. 2005;1046:180-186.
86. Dawe GS, Ratty AK. The Chakragati mouse: a mouse model for rapid in vivo screening of antipsychotic drug candidates. Biotechnol J. 2007;2:1344-1352.
87. Desbonnet L, Waddington JL, O'Tuathaigh CM. Mice mutant for genes associated with schizophrenia: common phenotype or distinct endophenotypes? Behav Brain Res. 2009;204:258-273.
88. Kirby B, Waddington JL, O'Tuathaigh CMP. Advancing a functional genomics for schizophrenia: psychopathological and cognitive phenotypes in mutants with gene disruption. Brain Res Bull. [published online ahead of print October 01, 2009].
89. Wise RA. Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res. 2008;14:169-183.
90. Coyle JT. Glutamate and schizophrenia: beyond the dopa-mine hypothesis. Cell Mol Neurobiol. 2006;26:365-384.
91. Pilowsky LS, Bressan RA, Stone JM, et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry. 2006;11:118-119.
92. Stone JM, Morrison PD, Pilowsky LS. Glutamate and dopamine dysregulation in schizophrenia\a synthesis and selective review. J Psychopharmacol. 2007;21:440-452.
93. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptorsasanew approachtotreat schizophrenia: a randomized phase 2 clinical trial. Nat Med. 2007;13:1102-1107.
94. Owen MJ, Craddock N, Jablensky A. The genetic decon-struction of psychosis. Schizophr Bull. 2007;33:905-911.
95. Mohn AR, Gainetdinov RR, Caron MG, Koller BH. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell. 1999;98:427-436.
96. Duncan GE, Moy SS, Perez A, Eddy DM, Zinzow WM, Lieberman JA. Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res. 2004;153:507-519.
97. Halene TB, Ehrlichman RS, Liang Y, et al. Assesssment of NMDAreceptorNR1subunithypofunctioninmiceasamodel for schizophrenia. Genes Brain Behav. 2009;8:661-675.
98. Labrie V, Lipina T, Roder JC. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology. 2008;200:217-230.
99. Boulay D, Pichat P, Dargazanli G, et al. Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia. Pharmacol Biochem Behav. 2008;91:47-58.
100. Tsai G, Yang P, Chung LC, Lange N, Coyle JT. D-serine added to antispsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998;44:1081-1089
101. Heresco-Levy U, Ermiloy M, LichtenbergP, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. 2004;55: 165-171.
102. Buchanan RW, Javitt DC, Marder SR, et al. The cognitive and negative symptoms in schizophrenia trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007;164:1593-1602.
103. Morrison PD, Pilowsky LS. Schizophrenia: more evidence for less glutamate. Expert Rev Neurother. 2007;7:29-31.
104. Guo X, Hamilton PJ, Reish NJ, Sweatt JD, Miller CA, Rumbaugh G. Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioural abnormalities that model symptoms of schizophrenia. Neuropsychopharmacology. 2009;34:1659-1672.
105. Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A. Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology. 2009;34:1578-1589.
106. Walsh T, McClellan JM, McCarthy SE, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320:539-543.
107. Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH. Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry. 2001;158:1393-1399.
108. Bauer D, Gupta D, Harotunian V, Meador-Woodruff JH, McCullumsmith RE. Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr Res. 2008;104:108-120.
109. Han L, Picker JD, Schaevitz LR, et al. Phenotypic characterization of mice heterozygous for a null mutation of gluta-mate carboxypeptidase II. Synapse. 2009;63:625-635.
110. Vekovischeva OY, Aitta-aho T, Verbitskaya E, Sandnabba K, Korpi ER. Acute effects of AMPA-type glutamate receptor antagonists on intermale social behaviour in two mouse lines bidirectionally selected for offensive aggression. Pharmacol Biochem Behav. 2007;87:241-249.
111. Wiedholz LM, Owens WA, Horton RE, et al. Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminer-gia and "schizophrenia- related" behaviors. Mol Psychiatry. 2008;13:631-640.
112. Krivoy A, Fischel T, Weizman A. The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol. 2008;18:395-405.
113. Shibata H, Tani A, Chikuhara T, Kikuta R, Sakai M, Nino-miya H. Association study of polymorphisms in the group III metabotropic glutamate receptor genes, GRM4 and GRM7, with schizophrenia. Psychiatr Res. 2009;167:88-96.
114. Navarro JF, Postigo D, Martin M, Buron E. Antiaggresive effects of MPEP, a selective antagonist of mGlu5 receptors, in agonistic interactions between male mice. Eur J Pharmacol. 2006;551:67-70.
115. Olszewski RT, Wegorzewska MM, Monteiro AC, et al. Phencyclidine and dizocilpine induced behaviours reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors. Biol Psychiatry. 2008;63: 86-91.
116. Takamori S, Rhee JS, Rosenmund C, Jahn R. Identification of a vesicular glutamate transporter that defines a glutama-tergic phenotype in neurons. Nature. 2000;407:189-194.
117. Fremeau RT Jr, Troyer MD, Pahner I, et al. The expression of vesicular glutamate transporters defies two classes of excitatory synapse. Neuron. 2001;31:247-260.
118. Herzog E, Bellenchi GC, Gras C, et al. The existence of a second vesicular glutamate transporter specifies subpopulations of glutamatergic neurons. J Neurosci. 2001;21:RC181.
119. Reynolds GP, Harte MK. The neuronal pathology of schizophrenia: molecules and mechanisms. Biochem Soc Trans. 2007;35:433-436.
120. Oni-Orisan A, Kristiansen LV, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE. Altered vesicular glutamate transporter expression in the anterior cingulate cortex in schizophrenia. Biol Psychiatry. 2008;63:766-775.
121. Garcia-Garcia AL, Elizalde N, Matrov D, et al. Increased vulnerability to depressive-like behaviour of mice with decreased expression of VGLUT1. Biol Psychiatry. 2009;66: 275-282.
122. Gogos JA. Schizophrenia susceptibility genes: in search of a molecular logic and novel drug targets for a devastating disorder. Int Rev Neurobiol. 2007;78:397-422.
123. Waddington JL, Corvin AP, Donohoe G, et al. Functional genomics and schizophrenia: endophenotypes and mutant models. Psychiatr Clin North Am. 2007;30:365-399.
124. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13:36-64.
125. Muir WJ, Pickard BS, Blackwood DH. Disrupted-in-schizophrenia-1. Curr Psychiatry Rep. 2008;10:140-147.
126. Shi J, Gershon ES, Liu C. Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. Schizophr Res. 2008;104:96-107.
127. Bertram L. Genetic research in schizophrenia: new tools and future perspectives. Schizophr Bull. 2008;34:806-812.
128. DeRosse P, Lencz T, Burdick KE, Siris SG, Kane JM, Malhotra AK. The genetics of symptom-based phenotypes: towards a molecular classification of schizophrenia. Schizophr Bull. 2008;34:1047-1053.
129. Purcell SM, Wray NR, et al. International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748-752.
130. Duan X, Chang JH, Ge S, et al. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007;130:1146-1158. (Pubitemid 47422304)
131. Tomppo L, Hennah W, Miettunen J, et al. Association of variants in DISC1 with psychosis-related traits in a large population cohort. Arch Gen Psychiatry. 2009;66:134-141.
132. Desbonnet L, Waddington JL, O'Tuathaigh CM. Mutant models for genes associated with schizophrenia. Biochem Soc Trans. 2009;37:308-312.
133. Clapcote SJ, Lipina TV, Millar JK, et al. Behavioral pheno-types of Disc1 missense mutations in mice. Neuron. 2007;54:387-402.
134. Li W, Zhou Y, Jentsch JD, Brown RAM, Tian X, Ehninger D. Specific developmental disruption of disrup-ted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci USA. 2007;104:18280-18285.
135. Hikida T, Jaaro-Peled H, Seshadri S, et al. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci USA. 2007;104:14501-14506.
136. Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioural abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2008;13: 173-186.
137. Weickert CS, Straub RE, McClintock BW, et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry. 2004;61:544-555.
138. Weickert CS, Rothmond DA, Hyde TM, Kleinman JE, Straub RE. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res. 2008;98:105-110.
139. Fanous AH, van den Oord EJ, Riley BP, et al. Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. Am J Psychiatry. 2005;162:1824-1832.
140. Li W, Zhang Q, Oiso N, et al. 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. 2003;35:84-89.
141. Feng YQ, Zhou ZY, He X, et al. Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. Schizophr Res. 2008;106: 218-228.
142. Shi J, Badner JA, Gershon ES, Liu C. Allelic association of G72/G30 with schizophrenia and bipolar disorder: a comprehensive meta-analysis. Schizophr Res. 2008;98:89-97.
143. Otte DM, Bilkei-Gorzo A, Filiou MD, et al. Behavioral changes in G72/G30 transgenic mice. Eur Neuropsychophar-macol. 2009;19:339-348.
144. Munafo MR, Attwood AS, Flint J. Neuregulin 1 genotype and schizophrenia. Schizophr Bull. 2008;34:9-12.
145. Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006;60:132-140.
146. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9:437-452.
147. O'Tuathaigh CMP, Desbonnet L, Waddington JL. Neure-gulin-1 signalling in schizophrenia: 'Jack of all trades' or master of some? Exp Rev Neurother. 2009;9:1-3.
148. O'Tuathaigh CM, Babovic D, O'Sullivan GJ, et al. Pheno-typic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1. Neuroscience. 2007;147:18-27.
149. Ehrlichman RS, Luminais SN, White SL, et al. Neuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions. Brain Res. 2009;1294:116-127.
150. Roy K, Murtie JC, El-Khodor BF, et al. Loss of ErbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci USA. 2007;104:8131-8136.
151. O'Tuathaigh CM, O'Connor AM, O'Sullivan GJ, et al. 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. 2008;32:462-466.
152. Chen YJ, Johnson MA, Lieberman MD, et al. Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci. 2008;28:6872-6883.
153. Barros CS, Calabrese B, Chamero P, et al. Impaired maturation of dendritic spines without disorganisation of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc Natl Acad Sci USA. 2009;106:4507-4512.
154. Hu X, Hicks CW, He W, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9:1520-1525.
155. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like pheno-types in BACE1-null mice. Proc Natl Acad Sci USA. 2008;105:5585-5590.
156. Miyakawa T, Leiter LM, Gerber DJ, et al. Conditional cal-cineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci USA. 2003;100:8987-8992.
157. Matsuo N, Tanda K, Nakanishi K, et al. Comprehensive behavioural phenotyping of ryanodine receptor type 3 (RyR3) knockout mice: decreased social contact duration in two social interaction tests. Front Behav Neurosci. 2009;3:1-7.
158. Talkowski ME, Seltman H, Bassett AS, et al. Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. Biol Psychiatry. 2006;60:152-162.
159. Lane HY, Liu YC, Huang CL, et al. RGS4 polymorphisms predict clinical manifestations and responses to risperidone treatment in patients with schizophrenia. J Clin Psychophar-macol. 2008;28:64-68.
160. Grillet N, Pattyn A, Contet C, Kieffer BL, Goridis C, Brunet JF. Generation and characterization of Rgs4 mutant mice. Mol Cell Biol. 2005;10:4221-4228.
161. McOmish CE, Burrows EL, Howard M, Hannan AJ. PLC-beta1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. Hippocampus. 2008;18:824-834.
162. Koh HY, Kim D, Lee J, Lee S, Shin H. Deficits in social behavior and sensorimotor gating in mice lacking phospholi-pase Cbeta1. Genes Brain Behav. 2008;7:120-128.
163. Van Os J, Rutten JP, Poulton R. Gene-environments in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull. 2008;34:1066-1082.
164. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40-68.
165. Drew CJ, Kyd RJ, Morton AJ. Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal. Hum Mol Genet. 2007;16:2288-2305.
166. Eastwood SL, Harrison PJ. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. Schizophr Res. 2005;73: 159-172.
167. Tueting P, Doueiri MS, Guidotti A, David JM, Costa E. Reelin down-regulation in mice and psychosis endopheno-types. Neurosci Biobehav Rev. 2006;30:1065-1077.
168. Salinger WL, Ladrow P, Wheeler C. Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation. Behav Neurosci. 2003;117:1257-1275.
169. Podhorna J, Didriksen M. The heterozygous reeler mouse: behavioural phenotype. Behav Brain Res. 2004;153:43-54.
170. Erbel-Sieler C, Dudley C, Zhou Y, et al. Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors. Proc Natl Acad Sci USA. 2004;101:13648-13653.
171. Tremolizzo L, Doueiri MS, Dong E, et al. Valproate corrects the schizophrenia-like epigenetic behavioural modifications induced by methionine in mice. Biol Psychiatry. 2005;57:500-509.
172. Begou M, Volle J, Bertrand JB, et al. The stop null mice model for schizophrenia displays [corrected] cognitive and social deficits partly alleviated by neuroleptics. Neuroscience. 2008;157:29-39.
173. Andrieux A, Salin P, Schweitzer A, et al. Microtubule stabilizer ameliorates synaptic function and behaviour in a mouse model for schizophrenia. Biol Psychiatry. 2006;60:1224-1230.
174. Dyck BA, Skoblenick KJ, Castellano KM, Ki K, Thomas N, Mishra RK. Synapsin II knockout mice show sensorimotor gating and behavioural abnormalities similar to those in the phencyclidine-induced preclinical animal model of schizophrenia. Schizophr Res. 2007;97:292-293.
175. Dyck BA, Skoblenick KJ, Castellano KM, Ki K, Thomas N, Mishra RK. Behavioral abnormalities in synapsin II knockout mice implicate a causal factor in schizophrenia. Synapse. 2009;63:662-672.
176. Insel TR. A neurobiological basis of social attachment. Am J Psychiatry. 1997;154:726-735.
177. Neumann ID. Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroen-docrinol. 2008;20:858-865.
178. Kirsch P, Esslinger C, Chen Q, et al. Oxytocin modulates neural circuitry for social recognition and fear in humans. J Neurosci. 2005;25:11489-11493.
179. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005;435: 673-676.
180. Popik P, van Ree JM. Oxytocin but not vasopressin facilitates social
181. Witt DM, Winslow JT, Insel TR. Enhanced social interactions in rats following chronic centrally infused oxytocin. Pharmacol Biochem Behav1. 1992;43:855-861.
182. Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI. Prenatal stress generates deficits in rat social behaviour: reversal by oxytocin. Brain Res. 2007;1156:152-167.
183. Lee HJ, Caldwell HK, Macbeth AH, Young WS, III. Behavioural studies using temporal and spatial inactivation of the oxytocin receptor. Prog Brain Res. 2008;170:73-77.
184. Macbeth AH, Lee HJ, Edds J, Young WS, III. Oxytocin and the oxytocin receptor underlie intrastrain, but not inter-strain, social recognition. Genes Brain Behav. 2009;8:558-567.
185. Uvnas-Moberg K, Alster P, Svensson TH. Amperozide and clozapine but not haloperidol or raclopride increase the secretion of oxytocin in rats. Psychopharmacology. 1992;109: 473-476.
186. Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology. 2004;29:483-493.
187. Bielsky IF, Hu SB, Young LJ. Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice. Behav Brain Res. 2005;164:132-136.
188. Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S, Takano Y. Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav Brain Res. 2007;178:123-127. (Pubitemid 46251426)
189. Wersinger SR, KelliherKR, ZufallF, LolaitSJ, O'Carroll AM, Young WS, III. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm Behav. 2004;46:638-645.
190. Wersinger SR, Caldwell HK, Christiansen M, Young WS, III. Disruption of the vasopressin 1B receptor gene impairs the attack component of aggressive behaviour in mice. Genes Brain Behav. 2007;6:653-660.
191. DeVito LM, Konigsberg R, Lykken C, Sauvage M, Young WS, III, Eichenbaum H. Vasopressin 1b receptor knockout impairs memory for temporal order. J Neurosci. 2009;29:2676-2683
192. Juch M, Small K-H, Kahne T, Lubec G, Tischmeyer W, Gundelfinger ED. Congenital lack of nNOS impairs long-term social recognition memory and alters the olfactory bulb proteome. Neurobiol Learn Mem. 2009;92:469-484.
193. Wass C, Klamer D, Fejgin K, Palsson E. The importance of nitric oxide in social dysfunction. Behav Brain Res. 2009;200: 113-116.
194. Fejgin K, Palsson E, Wass C, Svensson L, Klamer D. Nitric oxide signaling in the medial prefrontal cortex is involved in the biochemical and behavioral effects of phencyclidine. Neuropsychopharmacology. 2008;33:1874-1883.
195. Yang M, Clarke AM, Crawley JN. Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability. Eur J Neurosci. 2009;29:1663-1677.
196. Pietersen CY, Bosker FJ, Doorduin J, et al. An animal model of emotional blunting in schizophrenia. PLoS ONE. 2007;2:e1360.
197. Scattoni ML, Crawley J, Ricceri L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neu-rodevelopmental disorders. Neurosci Biobehav Rev. 2009;33:508-515.
198. Laviola G, Adriani W, Gaudino C, Marino R, Keller F. Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereo-typies in reeler mutant mice. Psychopharmacology. 2006;187: 331-344.
199. Shen S, Lang B, Nakamoto C, et al. Schizophrenia-related neural and behavioural phenotypes in transgenic mice expressing truncated DISC1. J Neurosci. 2008;28: 10893-10904.
200. Wang H, Liang S, Burgdorf J, Wess J, Yeomans J. Ultrasonic vocalizations induced by sex and amphetamine in M2, M4, M5 muscarinic and D2 dopamine receptor knockout mice. PLoS One. 2008;3:e1893.
201. Enard W, Gehre S, Hammerschmidt K, et al. A humanised version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell. 2009;137:961-971.
202. Chen J, Lipska BK, Weinberger DR. Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. Biol Psychiatry. 2006;59:1180-1188.
203. Kellendonk C, Simpson EH, Kandel ER. Modeling cognitive endophenotypes of schizophrenia in mice. Trends Neurosci. 2009;32:347-358.
204. Crabbe JC, Morris RG. Festina lente: late-night thoughts on high-throughput screening of mouse behaviour. Nat Neurosci. 2004;23:1175-1179.