Translational neuropsychiatry of genetic and neurodevelopmental animal models of schizophrenia;Estudos traducionais de neuropsiquiatria e esquizofrenia: Modelos animais genéticos e de neurodesenvolvimento

Revista de Psiquiatria Clinica

Volumn 40, Issue 1, 2013, Pages 41-50

  Gottschalk, Michael G ^a   Sarnyai, Zóltan ^a,b   Guest, Paul C ^a   Harris, Laura W ^a   Bahn, Sabine ^a,c  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b JAMES COOK UNIVERSITY   (Australia)

^c ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

Animal model; Genetic; Neurodevelopment; Neuropsychiatry; Schizophrenia; Translational research

Indexed keywords

4 AMINOBUTYRIC ACID RECEPTOR; DISRUPTED IN SCHIZOPHRENIA 1 PROTEIN; GLUTAMATE DECARBOXYLASE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NEU DIFFERENTIATION FACTOR; PROLINE DEHYDROGENASE; TUMOR NECROSIS FACTOR ALPHA;

BEHAVIOR; CONSTRUCT VALIDITY; DISEASE ASSOCIATION; EXPERIMENTAL ANIMAL; FACE VALIDITY; GENETIC ASSOCIATION; NERVE CELL DIFFERENTIATION; NERVOUS SYSTEM DEVELOPMENT; NEUROPSYCHIATRY; NEUROTRANSMISSION; NONHUMAN; PREDICTIVE VALIDITY; PREPULSE INHIBITION; REVIEW; SCHIZOPHRENIA; SIGNAL TRANSDUCTION;

EID: 84874374001     PISSN: 01016083     EISSN: 1806938X     Source Type: Journal    
DOI: 10.1590/S0101-60832012005000007     Document Type: Review

References (201)

1. WHO 2004. "The global burden of disease: 2004 update". Disponível em: .
2. McGrath JJ, Susser ES. New directions in the epidemiology of schizophrenia. Med J Aust. 2009;190(4 Suppl):S7-9.
3. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13(10):1161-9.
4. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158(9):1367-77.
5. Jones P, Rodgers B, Murray R, Marmot M. Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet. 1994;344(8934):1398-402.
6. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363(9426):2063-72.
7. Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 200510(5):434-49.
8. Swerdlow NR, Braff DL, Taaid N, Geyer MA. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry. 1994;51(2):139-54.
9. Marder SR, Fenton W. Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res. 2004;72(1):5-9.
10. Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004;72(1):29-39.
11. Mintz J, Kopelowicz A. CUtLASS confirms CATIE. Arch Gen Psychiatry. 2007;64(8):978; author reply 979-980.
12. Williams JH, Wellman NA, Geaney DP, Cowen PJ, Feldon J, Rawlins JN. Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment. Br J Psychiatry. 1998;172:243-9.
13. Rascle C, Mazas O, Vaiva G, Tournant M, Raybois O, Goudemand M, et al. Clinical features of latent inhibition in schizophrenia. Schizophr Res. 2001;51(2-3):149-61.
14. Nieoullon A. Dopamine and the regulation of cognition and attention. Prog Neurobiol. 2002;67(1):53-83.
15. Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990;47(2):181-8.
16. Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull. 2007;33(1):69-94.
17. Swerdlow NR, Lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA. Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats. Psychopharmacology (Berl). 1995;122(1):27-34.
18. Colacicco G, Welzl H, Lipp HP, Würbel H. Attentional set-shifting in mice: modification of a rat paradigm, and evidence for strain-dependent variation. Behav Brain Res. 2002;132(1):95-102.
19. McCarley RW, Wible CG, Frumin M, Hirayasu Y, Levitt JJ, Fischer IA, et al. MRI anatomy of schizophrenia. Biol Psychiatry. 1999;45(9):1099-119.
20. Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl). 2001;156(2-3):234-58.
21. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6(4):312-24.
22. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167(7):748-51.
23. Meltzer HY, Stahl SM. The dopamine hypothesis of schizophrenia: a review. Schizophr Bull. 1976;2(1):19-76.
24. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006;26(4-6):365-84.
25. Semkovska M, Bédard MA, Stip E. [Hypofrontality and negative symptoms in schizophrenia: synthesis of anatomic and neuropsychological knowledge and ecological perspectives]. Encephale. 2001;27(5):405-15.
26. Boyer P, Phillips JL, Rousseau FL, Ilivitsky S. Hippocampal abnormalities and memory deficits: new evidence of a strong pathophysiological link in schizophrenia. Brain Res Rev. 2007;54(1):92-112.
27. Geyer M, Markou A, editors. The role of preclinical models in the development of psychotropic drugs. Neuropsychopharmacology: The Fifth Generation of Progress. Washington, DC: American College of Neuropsychopharmacology; 2002.
28. Van der Staay FJ, Arndt SS, Nordquist RE. Evaluation of animal models of neurobehavioral disorders. Behav Brain Funct. 2009;5:11.
29. Kelly J, Murray RM. What risk factors tell us about the causes of schizophrenia and related psychoses. Curr Psychiatry Rep. 2000;2(5):378-85.
30. Mäki P, Veijola J, Jones PB, Murray GK, Koponen H, Tienari P, et al. Predictors of schizophrenia: a review. Br Med Bull. 2005;73-74:1-15.
31. Morgan C, Fisher H. Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma: a critical review. Schizophr Bull. 2007;33(1):3-10.
32. Kendler KS, Diehl SR. The genetics of schizophrenia: a current, geneticepidemiologic perspective. Schizophr Bull. 1993;19(2):261-85.
33. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187-92.
34. Maier W. Common risk genes for affective and schizophrenic psychoses. Eur Arch Psychiatry Clin Neurosci. 2008;258(Suppl 2):37-40.
35. Allen NC, Bagade S, McQueen MB, Ioannidis JPA, Kavvoura FK, Khoury MJ, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40(7):827-34.
36. Costa E, Davis J, Grayson DR, Guidotti A, Pappas GD, Pesold C. Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vulnerability. Neurobiol Dis. 2001;8(5):723-42.
37. O'Tuathaigh CM, Babovic D, O'Meara G, Clifford JJ, Croke DT, Waddington JL. Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. Neurosci Biobehav Rev. 2007;31(1):60-78.
38. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40-68; image 45.
39. Owen MJ, Craddock N, O'Donovan MC. Schizophrenia: genes at last? Trends Genet. 2005;21(9):518-25.
40. Karayiorgou M, Gogos JA. Schizophrenia genetics: uncovering positional candidate genes. Eur J Hum Genet. 2006;14(5):512-9.
41. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet. 1990;336(8706):13-6.
42. Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF. Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry. 2003;8(4):445-52.
43. Jaaro-Peled H. Gene models of schizophrenia: DISC1 mouse models. Prog Brain Res. 2009;179:75-86.
44. Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007;54(3):387-402.
45. Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006;103(10):3693-7.
46. Konarski JZ, McIntyre RS, Grupp LA, Kennedy SH. Is the cerebellum relevant in the circuitry of neuropsychiatric disorders? J Psychiatry Neurosci. 2005;30(3):178-86.
47. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006;52(1):139-53.
48. Schurov IL, Handford EJ, Brandon NJ, Whiting PJ. Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry. 2004;9(12):1100-10.
49. Arguello PA, Gogos JA. Modeling madness in mice: one piece at a time. Neuron. 2006;52(1):179-96.
50. Terrin A, Di Benedetto G, Pertegato V, Cheung YF, Baillie G, Lynch MJ, et al. PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. J Cell Biol. 2006;175(3):441-51.
51. Fatemi SH, King DP, Reutiman TJ, Folsom TD, Laurence JA, Lee S, et al. PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res. 2008;101(1-3):36-49.
52. Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, et al. Dominant-negative DISC1 transgenic mice display schizophreniaassociated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007;104(36):14501-16.
53. Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2008;13(2):173-86, 115.
54. Pogorelov VM, Nomura J, Kim J, Kannan G, Ayhan Y, Yang C, et al. Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model. Neuropharmacology. 2012;62(3):1242-51. Epub 2011 Feb 17.
55. Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B, et al. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci. 2004;25(1):42-55.
56. Eastwood SL. The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame? Int Rev Neurobiol. 2004;59:47-72.
57. Honer WG, Young CE. Presynaptic proteins and schizophrenia. Int Rev Neurobiol. 2004;59:175-99.
58. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, et al. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry. 2007;12(1):74-86.
59. Arnold SE, Franz BR, Gur RC, Gur RE, Shapiro RM, Moberg P, et al. Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry. 1995;152(5):738-48.
60. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006;11(5):514-22.
61. Kvajo M, McKellar H, Arguelo PA, Drew LJ, Moore H, MacDermott AB, et al. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A. 2008;105(19):7076-81.
62. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002;71(4):877-92.
63. Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006;60(2):32-40.
64. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9(6):437-52.
65. Van den Buuse M, Wischhof L, Lee RX, Martin S, Karl T. Neuregulin 1 hypomorphic mutant mice: enhanced baseline locomotor activity but normal psychotropic drug-induced hyperlocomotion and prepulse inhibition regulation. Int J Neuropsychopharmacol. 2009;12(10):1383-93.
66. Duffy L, Cappas E, Scimone A, Schofield PR, Karl T. Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin Behav Neurosci. 2008;122(4):748-59.
67. Deakin IH, Law AJ, Oliver PL, Schwab MH, Nave KA, Harrison PJ, et al. Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport. 2009;20(17):1523-8.
68. Wang XD, Su YA, Guo CM, Yang Y, Si TM. Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. Int J Neuropsychopharmacol. 2008;11(4):553-61.
69. Rimer M, Barrett DW, Maldonado MA, Vock VM, Gonzalez-Lima F. Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition. Neuroreport. 2005;16(3):271-5.
70. O'Tuathaigh CM, Babovic D, O'Sullivan GJ, Clifford JJ, Tighe O, et al. Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1. Neuroscience. 2007;147(1):18-27.
71. O'Tuathaigh CM, O'Connor AM, O'Sullivan GJ, Lai D, Harvey R, Croke DT, 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(2):462-6.
72. Ehrlichman RS, Luminais SN, White SL, Rudnick ND, Ma N, Dow HC, et al. Neuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions. Brain Res. 2009;1294:116-27.
73. Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H, et al. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/-knock-outs compared with wild-type mice. J Neurosci. 2007;27(17):4519-29.
74. Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004;56(5):301-7.
75. Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005;8(11):1586-94.
76. Sobin C, Kiley-Brabeck K, Daniels S, Khuri J, Taylor L, Blundell M, et al. Neuropsychological characteristics of children with the 22q11 Deletion Syndrome: a descriptive analysis. Child Neuropsychol. 2005;11(1):39-53.
77. Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS, et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis. 1994;182(8):476-8.
78. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56(10):940-45.
79. Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, et al. Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A. 2005;138(4):307-13.
80. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg C, Borrow J, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A. 1995;92(17):7612-6.
81. Usiskin SI, Nicolson R, Krasnewich DM, Yan W, Lenane M, Wudarsky M, et al. Velocardiofacial syndrome in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry. 1999;38(12):1536-43.
82. Pulver AE, Karayiorgou M, Lasseter VK, Wolyniec P, Kasch L, Antonarakis S, et al. Follow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1: Part 2. Am J Med Genet. 1994;54(1):44-50.
83. Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter VK, Kasch L, Nestadt G, et al. Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part Am J Med Genet. 1994;54(1):36-43.
84. Lasseter VK, Pulver AE, Wolyniec PS, Nestadt G, Meyers D, Karayiorgou M, et al. Follow-up report of potential linkage for schizophrenia on chromosome 22q: Part 3. Am J Med Genet. 1995;60(2):172-3.
85. Gogos JA, Santha M, Takacs Z, Beck KD, Luine V, Lucas LR, et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat Genet. 1999;21(4):434-9.
86. Fremeau RT Jr, Caron MG, Blakely RD. Molecular cloning and expression of a high affinity L-proline transporter expressed in putative glutamatergic pathways of rat brain. Neuron. 1992;8(5):915-26.
87. Cohen SM, JV Nadler. Proline-induced potentiation of glutamate transmission. Brain Res. 1997;761(2):271-82.
88. Renick SE, Kleven DT, Chan J, Stenius K, Milner TA, Pickel VM, et al. The mammalian brain high-affinity L-proline transporter is enriched preferentially in synaptic vesicles in a subpopulation of excitatory nerve terminals in rat forebrain. J Neurosci. 1999;19(1):21-33.
89. Kimber WL, Hsieh P, Hirotsune S, Yuva-Paylor L, Sutherland HF, Chen A, et al. Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum Mol Genet. 1999;8(12):2229-37.
90. Paylor R, McIlwain KL, McAninch R, Nellis A, Yuva-Paylor LA, Baldini A, et al. Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum Mol Genet. 2001;10(23):2645-50.
91. Long JM, LaPorte P, Merscher S, Funke B, Saint-Jore B, Puech A, et al. Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics. 2006;7(4):247-57.
92. Mukai J, Dhilla A, Drew LJ, Stark KL, Cao L, MacDermott AB, et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci. 2008;11(11):1302-10.
93. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008;40(6):751-60.
94. Meechan DW, Tucker ES, Maynard TM, LaMantia AS. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc Natl Acad Sci U S A. 2009;106(38):16434-45.
95. Karayiorgou M, Simon TJ, Gogos JA. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci. 2010;11(6):402-16.
96. 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(6566):606-12.
97. Gainetdinov RR, Jones SR, Fumagalli F, Wightman RM, Caron MG. Reevaluation of the role of the dopamine transporter in dopamine system homeostasis. Brain Res Brain Res Rev. 1998;26(2-3):148-53.
98. Dzirasa K, Santos LM, Ribeiro R, Stapleton J, Gainetdinov RR, Caron MG, et al. Persistent hyperdopaminergia decreases the peak frequency of hippocampal theta oscillations during quiet waking and REM sleep. PLoS One. 2009;4(4):e5238.
99. Hall FS, Li XF, Randall-Thompson J, Sora I, Murphy DL, Lesch KP, et al. Cocaine-conditioned locomotion in dopamine transporter, norepinephrine transporter and 5-HT transporter knockout mice. Neuroscience. 2009;162(4):870-80.
100. Pogorelov VM, Rodriguiz RM, Insco ML, Caron MG, Wetsel WC. Rodriguiz, et al. Novelty seeking and stereotypic activation of behavior in mice with disruption of the Dat1 gene. Neuropsychopharmacology. 2005;30(10):1818-31.
101. Wu N, Cepeda C, Zhuang X, Levine MS. Altered corticostriatal neurotransmission and modulation in dopamine transporter knock-down mice. J Neurophysiol. 2007;98(1):423-32. Epub 2007 May 23.
102. Bossé R, Fumagalli F, Jaber M, Giros B, Gainetdinov RR, Wetsel WC, et al. Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron. 1997;19(1):127-38.
103. Upadhyaya AR, El-Sheikh R, MacMaster FP, Diwadkar VA, Keshavan MS. Pituitary volume in neuroleptic-naive schizophrenia: a structural MRI study. Schizophr Res. 2007;90(1-3):266-73.
104. Mohn AR, Gainetdinov RR, Caron MG, Koller BH. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell. 1999;98(4):427-36.
105. Moy SS, Perez A, Koller BH, Duncan GE. Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function. Brain Res. 2006;1089(1):186-94.
106. Bickel S, Lipp HP, Umbricht D. Early auditory sensory processing deficits in mouse mutants with reduced NMDA receptor function. Neuropsychopharmacology. 2008;33(7):1680-9.
107. Korotkova T, Fuchs EC, Ponomarenko A, Von Engelhardt J, Monyer H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron. 2010;68(3):557-69.
108. Geyer MA, Swerdlow NR, Mansbach RS, Braff D. Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull. 1990;25(3):485-98.
109. Lodge DJ, Behrens MM, Grace AA. A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci. 2009;29(8):2344-54.
110. Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenialike phenotypes. Nat Neurosci. 2010;13(1):76-83.
111. Tsuang M. Schizophrenia: genes and environment. Biol Psychiatry. 2000;47(3):210-20.
112. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999;122(Pt 4):593-624.
113. Lipska BK, Jaskiw GE, Weinberger DR. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology. 1993.9(1):67-75.
114. Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry. 2006;60(3):253-64.
115. Berger N, Vaillancourt C, Boksa P. Genetic factors modulate effects of C-section birth on dopaminergic function in the rat. Neuroreport. 2000;11(3):639-43.
116. Fone KC, Porkess MV. Behavioural and neurochemical effects of postweaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev. 2008;32(6):1087-102.
117. Markham JA, Koenig JI. Prenatal stress: role in psychotic and depressive diseases. Psychopharmacology (Berl). 2011;214(1):89-106.
118. Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, et al. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry. 1999;4(2):145-54.
119. Steiger JL, Alexander MJ, Galler JR, Farb DH, Russek SJ. Effects of prenatal malnutrition on GABAA receptor alpha1, alpha3 and beta2 mRNA levels. Neuroreport. 2003;14(13):1731-5.
120. Flagstad P, Mørk A, Glenthøj BY, Van Beek J, Michael-Titus AT, Didriksen M. Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens. Neuropsychopharmacology. 2004;29(11):2052-64.
121. Palmer AA, Printz DJ, Butler PD, Dulawa SC, Printz MP. Prenatal protein deprivation in rats induces changes in prepulse inhibition and NMDA receptor binding. Brain Res. 2004;996(2):193-201.
122. Flagstad P, Glenthøj BY, Didriksen M. Cognitive deficits caused by late gestational disruption of neurogenesis in rats: a preclinical model of schizophrenia. Neuropsychopharmacology. 2005;30(2):250-60.
123. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J. Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. Neuropsychopharmacology. 2008;33(2):441-56.
124. Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, et al. A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J Neurosci. 2008;28(48):12691-9.
125. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45(2):189-92.
126. Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, Mors O, et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340(8):603-8.
127. Davies G, Welham J, Chant D, Torrey EF, Torrey J. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull. 2003;29(3):587-93.
128. Romero E, Guaza C, Castellano B, Borrell J. Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: implications for the etiopathology of schizophrenia. Mol Psychiatry. 2010;15(4):372-83.
129. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry. 2000;157(5):831-3.
130. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophr Res. 2001;52(1-2):101-5.
131. Kozlovsky N, Shanon-Weickert C, Tomaskovic-Crook E, Kleinman JE, Belmaker RH, Agam G. Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J Neural Transm. 2004;111(12):1583-92.
132. Monteleone P, Fabrazzo M, Tortorella A, Maj M. Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res. 1997;71(1):11-7.
133. Gaughran F. Immunity and schizophrenia: autoimmunity, cytokines, and immune responses. Int Rev Neurobiol. 2002;52:275-302.
134. Skurkovich SV, Aleksandrovsky YA, Chekhonin VP, Ryabukhin IA, Chakhava KO, Skurkovich B. Improvement in negative symptoms of schizophrenia with antibodies to tumor necrosis factor-alpha and to interferon-gamma: a case report. J Clin Psychiatry. 2003;64(6):734-5. 135. Romero E, Ali C, Molina-Holgado E, Castellano B, Guaza C, Borrell J. Neurobehavioral and immunological consequences of prenatal immune activation in rats. Influence of antipsychotics. Neuropsychopharmacology. 2007;32(8):1791-804.
135. Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003;23(1):297-302.
136. Cotter D, Takei N, Farrell M, Sham P, Quinn P, Larkin C, et al. Does prenatal exposure to influenza in mice induce pyramidal cell disarray in the dorsal hippocampus? Schizophr Res. 1995;16(3):233-41.
137. Altshuler LL, Conrad A, Kovelman JA, Scheibel A. Hippocampal pyramidal cell orientation in schizophrenia. A controlled neurohistologic study of the Yakovlev collection. Arch Gen Psychiatry. 1987;44(12):1094-8.
138. Christison GW, Casanova MF, Weinberger DR, Rawlings R, Kleinman JE. A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Arch Gen Psychiatry. 1989;46(11):1027-32.
139. Benes FM, Sorensen I, Bird ED. Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophr Bull. 1991;17(4):597-608.
140. Wright P, Murray RM. Schizophrenia: prenatal influenza and autoimmunity. Ann Med. 1993;25(5):497-502.
141. Müller N, Riedel M, Ackenheil M, Schwarz MJ. The role of immune function in schizophrenia: an overview. Eur Arch Psychiatry Clin Neurosci. 1999;249(Suppl 4):62-8.
142. Nawa H, Takahashi M, Patterson PH. Cytokine and growth factor involvement in schizophrenia: support for the developmental model. Mol Psychiatry. 2000;5(6):594-603.
143. Boin F, Zanardini R, et al. Association between-G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry. 2001;6(1):79-82.
144. Rothermundt M, Arolt V, Bayer TA. Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun. 2001;15(4):319-339.
145. Susser ES, Lin SP. Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Arch Gen Psychiatry. 1992;49(12):983-8.
146. Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry. 1996;53(1):25-31.
147. St Clair D, Xu M, Wang P, Yu Y, Fang Y, Zhang F, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA. 2005;294(5):557-62.
148. Palmer AA, Brown AS, Keegan D, Siska LD, Susser E, Rotrosen J, et al. Prenatal protein deprivation alters dopamine-mediated behaviors and dopaminergic and glutamatergic receptor binding. Brain Res. 2008;1237:62-74.
149. Chen JC, Turiak G, Galler J, Volicer L. Postnatal changes of brain monoamine levels in prenatally malnourished and control rats. Int J Dev Neurosci. 1997;15(2):257-63.
150. Stone JM, Morrison PD, Pilowsky LS. Glutamate and dopamine dysregulation in schizophrenia: a synthesis and selective review. J Psychopharmacol. 2007;21(4):440-52.
151. Tonkiss J, Galler JR. Prenatal protein malnutrition and working memory performance in adult rats. Behav Brain Res. 1990;40(2):95-107.
152. Barrett DE, Radke-Yarrow M. Effects of nutritional supplementation on children's responses to novel, frustrating, and competitive situations. Am J Clin Nutr. 1985;42(1):102-20.
153. Almeida SS, Tonkiss J, Galler JR. Prenatal protein malnutrition affects the social interactions of juvenile rats. Physiol Behav. 1996;60(1):197-201.
154. Marichich ES, Molina VA, Orsingher OA. Persistent changes in central catecholaminergic system after recovery of perinatally undernourished rats. J Nutr. 1979;109(6):1045-50.
155. Bayer S, Altman J, editors. Neurogenesis and neuronal migration. In: Paxinos G, editor. The rat nervous system. 2nd. San Diego, CA: Academic Press; 1995. p. 1041-78.
156. Gourevitch R, Rocher C, Le Pen G, Krebs MO, Jay TM. Working memory deficits in adult rats after prenatal disruption of neurogenesis. Behav Pharmacol. 2004;15(4):287-92.
157. Fiore M, Talamini L, Angelucci F, Koch T, Aloe L, Korf J. Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits. Neuropharmacology. 1999;38(6):857-69.
158. Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tusting P, et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci U S A. 2002;99(26):17095-100.
159. Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A. Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc Natl Acad Sci U S A. 2005;102(35):12578-83.
160. Selemon LD, Rajkowska G, Goldman-Rakic PS. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry. 1995;52(10):805-18; discussion 819-20.
161. Thune JJ, Pakkenberg B. Stereological studies of the schizophrenic brain. Brain Res Brain Res Rev. 2000;31(2-3):200-4.
162. Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000;157(1):16-25.
163. Ananth H, Popescu I, Critchley HD, Good CD, Frackowiak RS, Dolan RJ. Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry. Am J Psychiatry. 2002;159(9):1497-505.
164. Selemon LD, Mrzljak J, Kleinman JE, Herman MM, Goldman-Rakic PS. Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9. Arch Gen Psychiatry. 2003;60(1):69-77.
165. Jönsson SA, Luts A, Guldberg-Kjaer N, Ohman R. Pyramidal neuron size in the hippocampus of schizophrenics correlates with total cell count and degree of cell disarray. Eur Arch Psychiatry Clin Neurosci. 1999;249(4):169-73.
166. Hradetzky E, Sanderson TM, Tsang TM, Sherwood JL, Fitzjohn SM, Lakics V, et al. The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus. Neuropsychopharmacology. 2012;37(2):364-77.
167. Braff DL, Grillon C, Geyer MA. Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry. 1992;49(3):206-15.
168. Le Pen G, Gourevitch R, Hazane F, Hoareau C, Jay TM, Krebs MO. Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat. Neuroscience. 2006;143(2):395-405.
169. Aleman A, Hijman R, De Haan EH, Kahn RS. Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry. 1999;156(9):1358-66.
170. Heckers S, Curran T, Goff D, Rauch SL, Fischman AJ, Alpert NM, et al. Abnormalities in the thalamus and prefrontal cortex during episodic object recognition in schizophrenia. Biol Psychiatry. 2000;48(7):651-7.
171. Gray JA, Joseph MH, Hemsley DR, Young AM, Warburton EC, Boulenguez P, et al. The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia. Behav Brain Res. 1995;71(1-2):19-31.
172. Gray JA, Moran PM, Grigoryan G, Peters SL, Young AM, Joseph MH. Latent inhibition: the nucleus accumbens connection revisited. Behav Brain Res. 1997;88(1):27-34.
173. Stark H, Rothe T, Wagner T, Scheich H. Learning a new behavioral strategy in the shuttle-box increases prefrontal dopamine. Neuroscience. 2004;126(1):21-9.
174. Lavin A, Grace A. Effects of afferent stimulation and DA application on prefrontal cortical cells recorded intracellularly in vivo: comparisons between intact rats and rats with pharmacologically-induced disruption of cortical development. Soc Neurosci Abstr. 1997;23:2080.
175. Kosmidis MH, Breier A, Fantie BD. Avoidance learning in schizophrenia: a dissociation between the effects of aversive and non-aversive stimuli. Schizophr Res. 1999;38(1):51-9.
176. Le Pen G, Moreau JL. Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: reversal by clozapine, olanzapine and risperidone but not by haloperidol. Neuropsychopharmacology. 2002;27(1):1-11.
177. Lipska B, Weinberger D, editors. Cortical regulation of the mesolimbic dopamine system implications for schizophrenia. In: Kalivas PW, Barnes CD, editors. Limbic circuits and neuropsychiatry. Boca Raton: CRC Press; 1993.
178. Lipska BK, Weinberger DR. Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphineinduced stereotypic behaviors in the rat. Brain Res Dev Brain Res. 1993;75(2):213-22.
179. Chambers RA, Moore J, McEvoy JP, Levin ED. Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia. Neuropsychopharmacology. 1996;15(6):587-94.
180. Sams-Dodd F, Lipska BK, Weinberger DR. Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology (Berl). 1997;132(3):303-10.
181. Nuechterlein KH. Childhood precursors of adult schizophrenia. J Child Psychol Psychiatry. 1986;27(2):133-44.
182. Auerbach JG, Hans S, Marcus J. Neurobehavioral functioning and social behavior of children at risk for schizophrenia. Isr J Psychiatry Relat Sci. 1993;30(1):40-9.
183. Done DJ, Crow TJ, Johnstone EC, Sacker A. Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. BMJ. 1994;309(6956):699-703.
184. Sesack SR, Pickel VM. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol. 1992;320(2):145-60.
185. Stine CD, Lu W, Wolf ME. Expression of AMPA receptor flip and flop mRNAs in the nucleus accumbens and prefrontal cortex after neonatal ventral hippocampal lesions. Neuropsychopharmacology. 2001;24(3):253-66.
186. O'Donnell P, Lewis BL, Weinberger DR, Lipska BK. Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats. Cereb Cortex. 2002;12(9):975-82.
187. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23(15):6315-26.
188. Tordjman S, Drapier D, Bonnot O, Graignic R, Fortes S, Cohen D. Animal models relevant to schizophrenia and autism: validity and limitations. Behav Genet. 2007;37(1):61-78.
189. Kluge W, Alsaif M, Guest PC, Schwarz E, Bahn S. Translating potential biomarker candidates for schizophrenia and depression to animal models of psychiatric disorders. Expert Rev Mol Diagn. 2011;11(7):721-33.
190. Pechnick RN, George R, Poland RE. Characterization of the effects of the acute and repeated administration of MK-801 on the release of adrenocorticotropin, corticosterone and prolactin in the rat. Eur J Pharmacol. 1989;164(2):257-63.
191. Issa G, Wilson C, Terry AV Jr, Pillai A. An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies. Neurobiol Dis. 2010;39(3):327-33.
192. Borrell J, Vela JM, Arévalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002;26(2):204-15.
193. Mitsuhashi S, Fukushima T, Tomiya M, Santa T, Imai K, Toyo'oka T. Determination of kynurenine levels in rat plasma by high-performance liquid chromatography with pre-column fluorescence derivatization. Anal Chim Acta. 2007;584(2):315-21.
194. Tomiya M, Fukushima T, Kawai J, Aoyama C, Mitsuhashi S, Santa T, et al. Alterations of plasma and cerebrospinal fluid glutamate levels in rats treated with the N-methyl-D-aspartate receptor antagonist, ketamine. Biomed Chromatogr. 2006;20(6-7):628-33.
195. Minassian A, Henry BL, Geyer MA, Paulus MP, Young JW, Perry W. The quantitative assessment of motor activity in mania and schizophrenia. J Affect Disord. 2010;120(1-3):200-6.
196. Hellhammer D, Hero T, Gerhards F, Hellhammer J. Neuropattern: a new translational tool to detect and treat stress pathology. I. Strategical consideration. Stress. 2012;15(5):479-87. doi: 10.3109/10253890.2011.644604. Epub 2012 Jan 10.
197. Hennekam RC. Hereditary multiple exostoses. J Med Genet. 1991;28(4):262-6.
198. Sarnyai Z, Alsaif M, Bahn S, Ernst A, Guest PC, Hradetzky E, et al. Behavioral and molecular biomarkers in translational animal models for neuropsychiatric disorders. Int Rev Neurobiol. 2011;101:203-38.
199. Levin Y, Wang L, Schwarz E, Koethe D, Leweke FM, Bahn S. Global proteomic profiling reveals altered proteomic signature in schizophrenia serum. Mol Psychiatry. 2010;15(11):1088-100.
200. Schwarz E, Izmailov R, Spain M, Barnes A, Mapes JP, Guest PC, et al. Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia. Biomark Insights. 2010;5:39-47.
201. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. 2007;64(6):633-47.