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Psychiatry and Neuroscience Update pp 335–351Cite as

‘Two Hit’ Neurodevelopmental Mechanisms in Schizophrenia: Focus on Animal Models and the Role of BDNF

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Abstract

Schizophrenia is a serious mental illness which is characterized by a range of symptoms, including hallucinations and delusions, social withdrawal, and cognitive deficits. Brain neurotransmitter systems implicated in schizophrenia include subcortical and cortical dopaminergic and glutamatergic projections, with additional involvement of serotonin and cholinergic systems. Currently used antipsychotic drugs only provide relief in some symptomatic domains of schizophrenia and only in a proportion of patients. Therefore, there is an urgent need to better understand the mechanisms involved in the development of this illness.

Schizophrenia is most likely caused by a combination of genetic and environmental factors interacting in a ‘two hit’ longitudinal trajectory. This means that early factors, such as certain genetic polymorphisms, can cause increased vulnerability of the brain to environmental factors in late adolescence/young adulthood (e.g., stress or drugs of abuse). This combination might synergize to cause onset of the illness, whereas either of these ‘hits’ by themselves do not have this effect.

Brain-derived neurotrophic factor (BDNF) is involved in brain development and neural plasticity. In post-mortem studies, BDNF levels were found to be decreased in several parts of the brains of patients with schizophrenia and animal models of BDNF deficiency show behavioral changes with relevance to schizophrenia. In this chapter we will review evidence that altered BDNF levels could play a role in the ‘two hit’ interaction of early and late developmental factors in schizophrenia. These results could be important for the design of preventative or early intervention treatments in vulnerable individuals targeted at BDNF levels in the brain.

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References

  1. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363(9426):2063–72.

    Article  PubMed  Google Scholar 

  2. Angermeyer MC, Kuhn L, Goldstein JM. Gender and the course of schizophrenia: differences in treated outcomes. Schizophr Bull. 1990;16(2):293–307.

    Article  CAS  PubMed  Google Scholar 

  3. Häfner H. Gender differences in schizophrenia. Psychoneuroendocrinology. 2003;28 Suppl 2:17–54.

    Article  PubMed  Google Scholar 

  4. Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry. 2010;22(5):417–28.

    Article  PubMed  Google Scholar 

  5. Knapp M, Mangalore R, Simon J. The global costs of schizophrenia. Schizophr Bull. 2004;30(2):279–93.

    Article  PubMed  Google Scholar 

  6. World Health Organization. The world health report 2001. Geneva: World Health Organization; 2001.

    Google Scholar 

  7. Walker E, Kestler L, Bollini A, Hochman KM. Schizophrenia: etiology and course. Annu Rev Psychol. 2004;55:401–30.

    Article  PubMed  Google Scholar 

  8. Schultz SK, Andreasen NC. Schizophrenia. Lancet. 1999;353(9162):1425–30.

    Article  CAS  PubMed  Google Scholar 

  9. Mäkinen J, Miettunen J, Isohanni M, Koponen H. Negative symptoms in schizophrenia: a review. Nord J Psychiatry. 2008;62(5):334–41.

    Article  PubMed  Google Scholar 

  10. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41–51.

    Article  PubMed  Google Scholar 

  11. Keefe RS, Fenton WS. How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophr Bull. 2007;33(4):912–20.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Sponheim SR, Jung RE, Seidman LJ, Mesholam-Gately RI, Manoach DS, O’Leary DS, Ho BC, Andreasen NC, Lauriello J, Schulz SC. Cognitive deficits in recent-onset and chronic schizophrenia. J Psychiatr Res. 2010;44(7):421–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Heaton RK, Gladsjo JA, Palmer BW, Kuck J, Marcotte TD, Jeste DV. Stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry. 2001;58(1):24–32.

    Article  CAS  PubMed  Google Scholar 

  14. Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005;8(3):457–72.

    Article  CAS  PubMed  Google Scholar 

  15. Weinberger DR, Torrey EF, Neophytides AN, Wyatt RJ. Lateral cerebral ventricular enlargement in chronic schizophrenia. Arch Gen Psychiatry. 1979;36(7):735–9.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry. 1998;172:110–20.

    Article  CAS  PubMed  Google Scholar 

  18. Konick LC, Friedman L. Meta-analysis of thalamic size in schizophrenia. Biol Psychiatry. 2001;49(1):28–38.

    Article  CAS  PubMed  Google Scholar 

  19. Adriano F, Caltagirone C, Spalletta G. Hippocampal volume reduction in first-episode and chronic schizophrenia: a review and meta-analysis. Neuroscientist. 2012;18(2):180–200.

    Article  PubMed  Google Scholar 

  20. Nelson MD, Saykin AJ, Flashman LA, Riordan HJ. Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry. 1998;55(5):433–40.

    Article  CAS  PubMed  Google Scholar 

  21. Velakoulis D, Pantelis C, McGorry PD, Dudgeon P, Brewer W, Cook M, Desmond P, Bridle N, Tierney P, Murrie V, Singh B, Copolov D. Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry. 1999;56(2):133–41.

    Article  CAS  PubMed  Google Scholar 

  22. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry. 2006;188:510–8.

    Article  PubMed  Google Scholar 

  23. Glahn DC, Ragland JD, Abramoff A, Barrett J, Laird AR, Bearden CE, Velligan DI. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005;25(1):60–9.

    Article  PubMed  Google Scholar 

  24. Jessen F, Scheef L, Germeshausen L, Tawo Y, Kockler M, Kuhn KU, Maier W, Schild HH, Heun R. Reduced hippocampal activation during encoding and recognition of words in schizophrenia patients. Am J Psychiatry. 2003;160(7):1305–12.

    Article  PubMed  Google Scholar 

  25. Rametti G, Junque C, Vendrell P, Catalan R, Penades R, Bargallo N, Bernardo M. Hippocampal underactivation in an fMRI study of word and face memory recognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2009;259(4):203–11.

    Article  PubMed  Google Scholar 

  26. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999;122:593–624.

    Article  PubMed  Google Scholar 

  27. Abi-Dargham A. Do we still believe in the dopamine hypothesis? New data bring new evidence. Int J Neuropsychopharmacol. 2004;7 Suppl 1:S1–5.

    Article  CAS  PubMed  Google Scholar 

  28. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148(11):1474–86.

    Article  CAS  PubMed  Google Scholar 

  29. Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M. Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry. 2009;65(12):1091–3.

    Article  CAS  PubMed  Google Scholar 

  30. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998;155(6):761–7.

    CAS  PubMed  Google Scholar 

  31. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46(1):56–72.

    Article  CAS  PubMed  Google Scholar 

  32. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA. 2000;97(14):8104–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Williams GV, Castner SA. Under the curve: critical issues for elucidating D1 receptor function in working memory. Neuroscience. 2006;139(1):263–76.

    Article  CAS  PubMed  Google Scholar 

  34. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301–8.

    Article  CAS  PubMed  Google Scholar 

  35. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006;26(4–6):365–84.

    CAS  PubMed  Google Scholar 

  36. Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry. 2013;18(11):1185–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69–108.

    Article  CAS  PubMed  Google Scholar 

  38. Blum BP, Mann JJ. The GABAergic system in schizophrenia. Int J Neuropsychopharmacol. 2002;5(2):159–79.

    Article  CAS  PubMed  Google Scholar 

  39. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000;57(11):1061–9.

    Article  CAS  PubMed  Google Scholar 

  40. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry. 2000;57(3):237–45.

    Article  CAS  PubMed  Google Scholar 

  41. Thompson Ray M, Weickert CS, Wyatt E, Webster MJ. Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci. 2011;36(3):195–203.

    Article  PubMed  Google Scholar 

  42. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23(15):6315–26.

    CAS  PubMed  Google Scholar 

  43. Abi-Dargham A. Alterations of serotonin transmission in schizophrenia. Int Rev Neurobiol. 2007;78:133–64.

    Article  CAS  PubMed  Google Scholar 

  44. Berman JA, Talmage DA, Role LW. Cholinergic circuits and signaling in the pathophysiology of schizophrenia. Int Rev Neurobiol. 2007;78:193–223.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, "just the facts" 5. Treatment and prevention. Past, present, and future. Schizophr Res. 2010;122(1–3):1–23.

    Article  PubMed  Google Scholar 

  46. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10(1):79–104.

    Article  CAS  PubMed  Google Scholar 

  47. Harvey PD, Rabinowitz J, Eerdekens M, Davidson M. Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial. Am J Psychiatry. 2005;162(10):1888–95.

    Article  PubMed  Google Scholar 

  48. Lindenmayer JP, Khan A, Iskander A, Abad MT, Parker B. A randomized controlled trial of olanzapine versus haloperidol in the treatment of primary negative symptoms and neurocognitive deficits in schizophrenia. J Clin Psychiatry. 2007;68(3):368–79.

    Article  CAS  PubMed  Google Scholar 

  49. Keefe RS, Silva SG, Perkins DO, Lieberman JA. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull. 1999;25(2):201–22.

    Article  CAS  PubMed  Google Scholar 

  50. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. 2007;64(6):633–47.

    Article  CAS  PubMed  Google Scholar 

  51. Keefe RS, Seidman LJ, Christensen BK, Hamer RM, Sharma T, Sitskoorn MM, Lewine RR, Yurgelun-Todd DA, Gur RC, Tohen M, Tollefson GD, Sanger TM, Lieberman JA. Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry. 2004;161(6):985–95.

    Article  PubMed  Google Scholar 

  52. Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, Reimherr F, McGee MF, Keefe RS, McEvoy JP, Hsiao JK, Lieberman JA. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry. 2007;164(3):428–36.

    Article  PubMed  Google Scholar 

  53. McGuffin P, Owen MJ, Farmer AE. Genetic basis of schizophrenia. Lancet. 1995;346(8976):678–82.

    Article  CAS  PubMed  Google Scholar 

  54. Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, Venturi P, Jones LA, Lewis SW, Sham PC, Gottesman II, Farmer AE, McGuffin P, Reveley AM, Murray RM. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry. 1999;56(2):162–8.

    Article  CAS  PubMed  Google Scholar 

  55. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40–68.

    Article  CAS  PubMed  Google Scholar 

  56. Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. Am J Psychiatry. 1998;155(3):355–64.

    Article  CAS  PubMed  Google Scholar 

  57. Wright P, Takei N, Rifkin L, Murray RM. Maternal influenza, obstetric complications, and schizophrenia. Am J Psychiatry. 1995;152(12):1714–20.

    Article  CAS  PubMed  Google Scholar 

  58. Brown AS, Susser ES. Prenatal nutritional deficiency and risk of adult schizophrenia. Schizophr Bull. 2008;34(6):1054–63.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Agid O, Shapira B, Zislin J, Ritsner M, Hanin B, Murad H, Troudart T, Bloch M, Heresco-Levy U, Lerer B. Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Mol Psychiatry. 1999;4(2):163–72.

    Article  CAS  PubMed  Google Scholar 

  60. Anglin DM, Cohen PR, Chen H. Duration of early maternal separation and prediction of schizotypal symptoms from early adolescence to midlife. Schizophr Res. 2008;103(1–3):143–50.

    Article  PubMed Central  PubMed  Google Scholar 

  61. Alvarez MJ, Roura P, Oses A, Foguet Q, Sola J, Arrufat FX. Prevalence and clinical impact of childhood trauma in patients with severe mental disorders. J Nerv Ment Dis. 2011;199(3):156–61.

    Article  PubMed  Google Scholar 

  62. Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005;112(5):330–50.

    Article  CAS  PubMed  Google Scholar 

  63. Whitfield CL, Dube SR, Felitti VJ, Anda RF. Adverse childhood experiences and hallucinations. Child Abuse Negl. 2005;29(7):797–810.

    Article  PubMed  Google Scholar 

  64. Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004;109(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  65. Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry. 2001;58(11):1039–46.

    Article  CAS  PubMed  Google Scholar 

  66. Walker EF, Diforio D. Schizophrenia: a neural diathesis-stress model. Psychol Rev. 1997;104(4):667–85.

    Article  CAS  PubMed  Google Scholar 

  67. Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L, Malaspina D. The stress cascade and schizophrenia: etiology and onset. Schizophr Bull. 2003;29(4):671–92.

    Article  PubMed  Google Scholar 

  68. Myin-Germeys I, van Os J, Schwartz JE, Stone AA, Delespaul PA. Emotional reactivity to daily life stress in psychosis. Arch Gen Psychiatry. 2001;58(12):1137–44.

    Article  CAS  PubMed  Google Scholar 

  69. Pariante CM, Vassilopoulou K, Velakoulis D, Phillips L, Soulsby B, Wood SJ, Brewer W, Smith DJ, Dazzan P, Yung AR, Zervas IM, Christodoulou GN, Murray R, McGorry PD, Pantelis C. Pituitary volume in psychosis. Br J Psychiatry. 2004;185:5–10.

    Article  PubMed  Google Scholar 

  70. Garner B, Pariante CM, Wood SJ, Velakoulis D, Phillips L, Soulsby B, Brewer WJ, Smith DJ, Dazzan P, Berger GE, Yung AR, van den Buuse M, Murray R, McGorry PD, Pantelis C. Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis. Biol Psychiatry. 2005;58(5):417–23.

    Article  PubMed  Google Scholar 

  71. Blanchard JJ, Brown SA, Horan WP, Sherwood AR. Substance use disorders in schizophrenia: review, integration, and a proposed model. Clin Psychol Rev. 2000;20(2):207–34.

    Article  CAS  PubMed  Google Scholar 

  72. Cassano GB, Pini S, Saettoni M, Rucci P, Dell’Osso L. Occurrence and clinical correlates of psychiatric comorbidity in patients with psychotic disorders. J Clin Psychiatry. 1998;59(2):60–8.

    Article  CAS  PubMed  Google Scholar 

  73. McCreadie RG. Use of drugs, alcohol and tobacco by people with schizophrenia: case-control study. Br J Psychiatry. 2002;181:321–5.

    Article  PubMed  Google Scholar 

  74. Gururajan A, Manning EE, Klug M, van den Buuse M. Drugs of abuse and increased risk of psychosis development. Aust N Z J Psychiatry. 2012;46(12):1120–35.

    Article  PubMed  Google Scholar 

  75. Walker EF, Savoie T, Davis D. Neuromotor precursors of schizophrenia. Schizophr Bull. 1994;20(3):441–51.

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Chua SE, Murray RM. The neurodevelopmental theory of schizophrenia: evidence concerning structure and neuropsychology. Ann Med. 1996;28(6):547–55.

    Article  CAS  PubMed  Google Scholar 

  78. Pantelis C, Yucel M, Wood SJ, McGorry PD, Velakoulis D. Early and late neurodevelopmental disturbances in schizophrenia and their functional consequences. Aust N Z J Psychiatry. 2003;37(4):399–406.

    Article  PubMed  Google Scholar 

  79. Murray RM, Fearon P. The developmental ‘risk factor’ model of schizophrenia. J Psychiatr Res. 1999;33(6):497–9.

    Article  CAS  PubMed  Google Scholar 

  80. McGrath JJ, Feron FP, Burne TH, Mackay-Sim A, Eyles DW. The neurodevelopmental hypothesis of schizophrenia: a review of recent developments. Ann Med. 2003;35(2):86–93.

    Article  PubMed  Google Scholar 

  81. Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia. Schizophr Bull. 2001;27(3):457–76.

    Article  CAS  PubMed  Google Scholar 

  82. Bayer TA, Falkai P, Maier W. Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the "two hit hypothesis". J Psychiatr Res. 1999;33(6):543–8.

    Article  CAS  PubMed  Google Scholar 

  83. Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci. 2006;7(7):583–90.

    Article  CAS  PubMed  Google Scholar 

  84. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005;57(10):1117–27.

    Article  CAS  PubMed  Google Scholar 

  85. Henquet C, Rosa A, Delespaul P, Papiol S, Fananas L, van Os J, Myin-Germeys I. COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of ‘switching’ on hallucinations in the flow of daily life. Acta Psychiatr Scand. 2009;119(2):156–60.

    Article  CAS  PubMed  Google Scholar 

  86. Stefanis NC, Henquet C, Avramopoulos D, Smyrnis N, Evdokimidis I, Myin-Germeys I, Stefanis CN, Van Os J. COMT Val158Met moderation of stress-induced psychosis. Psychol Med. 2007;37(11):1651–6.

    Article  PubMed  Google Scholar 

  87. Kantrowitz JT, Nolan KA, Sen S, Simen AA, Lachman HM, Bowers Jr MB. Adolescent cannabis use, psychosis and catechol-O-methyltransferase genotype in African Americans and Caucasians. Psychiatr Q. 2009;80(4):213–8.

    Article  PubMed Central  PubMed  Google Scholar 

  88. Zammit S, Spurlock G, Williams H, Norton N, Williams N, O’Donovan MC, Owen MJ. Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry. 2007;191:402–7.

    Article  PubMed  Google Scholar 

  89. Notaras M, Hill R, van den Buuse M. A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev. 2015;51(4):15–30.

    Article  CAS  PubMed  Google Scholar 

  90. Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R. Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl). 1997;132(2):107–24.

    Article  CAS  Google Scholar 

  91. van den Buuse M. Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull. 2010;36(2):246–70.

    Article  PubMed Central  PubMed  Google Scholar 

  92. Hori T, Subramaniam S, Srivastava LK, Quirion R. Behavioral and neurochemical alterations following repeated phencyclidine administration in rats with neonatal ventral hippocampal lesions. Neuropharmacology. 2000;39(12):2478–91.

    Article  CAS  PubMed  Google Scholar 

  93. Schneider M, Koch M. The effect of chronic peripubertal cannabinoid treatment on deficient object recognition memory in rats after neonatal mPFC lesion. Eur Neuropsychopharmacol. 2007;17(3):180–6.

    Article  CAS  PubMed  Google Scholar 

  94. Ashby DM, Habib D, Dringenberg HC, Reynolds JN, Beninger RJ. Subchronic MK-801 treatment and post-weaning social isolation in rats: differential effects on locomotor activity and hippocampal long-term potentiation. Behav Brain Res. 2010;212(1):64–70.

    Article  CAS  PubMed  Google Scholar 

  95. Ellenbroek BA, Cools AR. Early maternal deprivation and prepulse inhibition: the role of the postdeprivation environment. Pharmacol Biochem Behav. 2002;73(1):177–84.

    Article  CAS  PubMed  Google Scholar 

  96. Niwa M, Matsumoto Y, Mouri A, Ozaki N, Nabeshima T. Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. Int J Neuropsychopharmacol. 2011;14(4):459–77.

    Article  PubMed  Google Scholar 

  97. Garner B, Wood SJ, Pantelis C, van den Buuse M. Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: no further effect of post-pubertal chronic corticosterone treatment. Behav Brain Res. 2007;176(2):323–32.

    Article  CAS  PubMed  Google Scholar 

  98. Choy KH, de Visser Y, Nichols NR, van den Buuse M. Combined neonatal stress and young-adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: effects on learning and memory. Hippocampus. 2008;18(7):655–67.

    Article  CAS  PubMed  Google Scholar 

  99. Choy KH, de Visser YP, van den Buuse M. The effect of ‘two hit’ neonatal and young-adult stress on dopaminergic modulation of prepulse inhibition and dopamine receptor density. Br J Pharmacol. 2009;156(2):388–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Choy KH, van den Buuse M. Attenuated disruption of prepulse inhibition by dopaminergic stimulation after maternal deprivation and adolescent corticosterone treatment in rats. Eur Neuropsychopharmacol. 2008;18(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  101. Llorente R, Miguel-Blanco C, Aisa B, Lachize S, Borcel E, Meijer OC, Ramirez MJ, De Kloet ER, Viveros MP. Long term sex-dependent psychoneuroendocrine effects of maternal deprivation and juvenile unpredictable stress in rats. J Neuroendocrinol. 2011;23(4):329–44.

    Article  CAS  PubMed  Google Scholar 

  102. Llorente-Berzal A, Fuentes S, Gagliano H, Lopez-Gallardo M, Armario A, Viveros MP, Nadal R. Sex-dependent effects of maternal deprivation and adolescent cannabinoid treatment on adult rat behaviour. Addict Biol. 2011;16(4):624–37.

    Article  CAS  PubMed  Google Scholar 

  103. Zamberletti E, Prini P, Speziali S, Gabaglio M, Solinas M, Parolaro D, Rubino T. Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats. Neuroscience. 2012;204:245–57.

    Article  CAS  PubMed  Google Scholar 

  104. Klug M, van den Buuse M. Chronic cannabinoid treatment during young adulthood induces sex-specific behavioural deficits in maternally separated rats. Behav Brain Res. 2012;233(2):305–13.

    Article  CAS  PubMed  Google Scholar 

  105. Desbonnet L, O’Tuathaigh C, Clarke G, O’Leary C, Petit E, Clarke N, Tighe O, Lai D, Harvey R, Cryan JF, Dinan TG, Waddington JL. Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene x environment interaction. Brain Behav Immun. 2012;26(4):660–71.

    Article  CAS  PubMed  Google Scholar 

  106. Boucher AA, Arnold JC, Duffy L, Schofield PR, Micheau J, Karl T. Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology (Berl). 2007;192(3):325–36.

    Article  CAS  Google Scholar 

  107. Long LE, Chesworth R, Arnold JC, Karl T. A follow-up study: acute behavioural effects of Delta(9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice. Psychopharmacology (Berl). 2010;211(3):277–89.

    Article  CAS  Google Scholar 

  108. Boucher AA, Hunt GE, Micheau J, Huang X, McGregor IS, Karl T, Arnold JC. The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. Int J Neuropsychopharmacol. 2011;14(5):631–43.

    Article  CAS  PubMed  Google Scholar 

  109. Long LE, Chesworth R, Huang XF, McGregor IS, Arnold JC, Karl T. Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence. Int J Neuropsychopharmacol. 2012;16:163–75.

    Article  PubMed  CAS  Google Scholar 

  110. O’Tuathaigh CM, Hryniewiecka M, Behan A, Tighe O, Coughlan C, Desbonnet L, Cannon M, Karayiorgou M, Gogos JA, Cotter DR, Waddington JL. Chronic adolescent exposure to Delta-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes. Neuropsychopharmacology. 2010;35(11):2262–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  111. O’Tuathaigh CM, Clarke G, Walsh J, Desbonnet L, Petit E, O’Leary C, Tighe O, Clarke N, Karayiorgou M, Gogos JA, Dinan TG, Cryan JF, Waddington JL. Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes. Int J Neuropsychopharmacol. 2011;15:1331–42.

    Article  PubMed  CAS  Google Scholar 

  112. Ognibene E, Adriani W, Caprioli A, Ghirardi O, Ali SF, Aloe L, Laviola G. The effect of early maternal separation on brain derived neurotrophic factor and monoamine levels in adult heterozygous reeler mice. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(5):1269–76.

    Article  CAS  PubMed  Google Scholar 

  113. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677–736.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. McAllister AK, Katz LC, Lo DC. Neurotrophins and synaptic plasticity. Annu Rev Neurosci. 1999;22:295–318.

    Article  CAS  PubMed  Google Scholar 

  115. Lu B, Chow A. Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res. 1999;58(1):76–87.

    Article  CAS  PubMed  Google Scholar 

  116. Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T. Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res. 2007;85(3):525–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Lessmann V, Gottmann K, Malcangio M. Neurotrophin secretion: current facts and future prospects. Prog Neurobiol. 2003;69(5):341–74.

    Article  CAS  PubMed  Google Scholar 

  118. Messaoudi E, Ying SW, Kanhema T, Croll SD, Bramham CR. Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. J Neurosci. 2002;22(17):7453–61.

    CAS  PubMed  Google Scholar 

  119. Yoshii A, Constantine-Paton M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol. 2010;70(5):304–22.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31–9.

    Article  CAS  PubMed  Google Scholar 

  121. Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M. Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron. 1992;9(6):1081–8.

    Article  CAS  PubMed  Google Scholar 

  122. Lu Y, Christian K, Lu B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem. 2008;89(3):312–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92(19):8856–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Korte M, Griesbeck O, Gravel C, Carroll P, Staiger V, Thoenen H, Bonhoeffer T. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci USA. 1996;93(22):12547–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306(5695):487–91.

    Article  CAS  PubMed  Google Scholar 

  126. Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci. 2000;20(18):7116–21.

    CAS  PubMed  Google Scholar 

  127. Kesslak JP, So V, Choi J, Cotman CW, Gomez-Pinilla F. Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance? Behav Neurosci. 1998;112(4):1012–9.

    Article  CAS  PubMed  Google Scholar 

  128. Cirulli F, Berry A, Chiarotti F, Alleva E. Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus. 2004;14(7):802–7.

    Article  CAS  PubMed  Google Scholar 

  129. Ma YL, Wang HL, Wu HC, Wei CL, Lee EH. Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience. 1998;82(4):957–67.

    Article  CAS  PubMed  Google Scholar 

  130. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64(2):238–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  131. Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P, Thome J. Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res. 2001;52(1–2):79–86.

    Article  CAS  PubMed  Google Scholar 

  132. Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K, Koizumi S, Wakabayashi K, Takahashi H, Someya T, Nawa H. Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry. 2000;5(3):293–300.

    Article  CAS  PubMed  Google Scholar 

  133. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci. 2005;25(2):372–83.

    Article  CAS  PubMed  Google Scholar 

  134. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry. 2003;8(6):592–610.

    Article  CAS  PubMed  Google Scholar 

  135. Weickert CS, Ligons DL, Romanczyk T, Ungaro G, Hyde TM, Herman MM, Weinberger DR, Kleinman JE. Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol Psychiatry. 2005;10(7):637–50.

    Article  CAS  PubMed  Google Scholar 

  136. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology. 1998;37(12):1553–61.

    Article  CAS  PubMed  Google Scholar 

  137. Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry. 2011;16(9):960–72.

    Article  CAS  PubMed  Google Scholar 

  138. Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61(7):911–22.

    Article  CAS  PubMed  Google Scholar 

  139. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry. 2005;10(2):208–12.

    Article  CAS  PubMed  Google Scholar 

  140. Rosa A, Cuesta MJ, Fatjo-Vilas M, Peralta V, Zarzuela A, Fananas L. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with risk for psychosis: evidence from a family-based association study. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(2):135–8.

    Article  PubMed  Google Scholar 

  141. Numata S, Ueno S, Iga J, Yamauchi K, Hongwei S, Ohta K, Kinouchi S, Shibuya-Tayoshi S, Tayoshi S, Aono M, Kameoka N, Sumitani S, Tomotake M, Kaneda Y, Taniguchi T, Ishimoto Y, Ohmori T. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. Neurosci Lett. 2006;401(1–2):1–5.

    Article  CAS  PubMed  Google Scholar 

  142. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004;24(18):4401–11.

    Article  CAS  PubMed  Google Scholar 

  143. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257–69.

    Article  CAS  PubMed  Google Scholar 

  144. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003;23(17):6690–4.

    CAS  PubMed  Google Scholar 

  145. Hajek T, Kopecek M, Höschl C. Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: meta-analysis. World J Biol Psychiatry. 2012;13(3):178–87.

    Article  PubMed  Google Scholar 

  146. Kanazawa T, Glatt SJ, Kia-Keating B, Yoneda H, Tsuang MT. Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatr Genet. 2007;17(3):165–70.

    Article  PubMed  Google Scholar 

  147. Yi Z, Zhang C, Wu Z, Hong W, Li Z, Fang Y, Yu S. Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population. Brain Res. 2011;1417:146–50.

    Article  CAS  PubMed  Google Scholar 

  148. Ernfors P, Lee KF, Jaenisch R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature. 1994;368(6467):147–50.

    Article  CAS  PubMed  Google Scholar 

  149. Hill RA, van den Buuse M. Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice. Brain Res. 2011;1384:51–60.

    Article  CAS  PubMed  Google Scholar 

  150. Dluzen DE, Gao X, Story GM, Anderson LI, Kucera J, Walro JM. Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/- BDNF mutant mice. Exp Neurol. 2001;170(1):121–8.

    Article  CAS  PubMed  Google Scholar 

  151. Saylor AJ, McGinty JF. Amphetamine-induced locomotion and gene expression are altered in BDNF heterozygous mice. Genes Brain Behav. 2008;7(8):906–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  152. Kernie SG, Liebl DJ, Parada LF. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 2000;19(6):1290–300.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  153. Chourbaji S, Hellweg R, Brandis D, Zorner B, Zacher C, Lang UE, Henn FA, Hörtnagl H, Gass P. Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Brain Res Mol Brain Res. 2004;121(1–2):28–36.

    Article  CAS  PubMed  Google Scholar 

  154. MacQueen GM, Ramakrishnan K, Croll SD, Siuciak JA, Yu G, Young LT, Fahnestock M. Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. Behav Neurosci. 2001;115(5):1145–53.

    Article  CAS  PubMed  Google Scholar 

  155. Linnarsson S, Björklund A, Ernfors P. Learning deficit in BDNF mutant mice. Eur J Neurosci. 1997;9(12):2581–7.

    Article  CAS  PubMed  Google Scholar 

  156. Montkowski A, Holsboer F. Intact spatial learning and memory in transgenic mice with reduced BDNF. Neuroreport. 1997;8(3):779–82.

    Article  CAS  PubMed  Google Scholar 

  157. Liu IY, Lyons WE, Mamounas LA, Thompson RF. Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning. J Neurosci. 2004;24(36):7958–63.

    Article  CAS  PubMed  Google Scholar 

  158. Gorski JA, Balogh SA, Wehner JM, Jones KR. Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice. Neuroscience. 2003;121(2):341–54.

    Article  CAS  PubMed  Google Scholar 

  159. Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, Meuth S, Nagy A, Greene RW, Nestler EJ. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA. 2004;101(29):10827–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 2007;12(7):656–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  161. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL, Lee FS. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314(5796):140–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  162. Spencer JL, Waters EM, Milner TA, Lee FS, McEwen BS. BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function. Proc Natl Acad Sci USA. 2010;107(9):4395–400.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  163. Klug M, Hill RA, Choy KH, Kyrios M, Hannan AJ, van den Buuse M. Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice. Neurobiol Dis. 2012;46(3):722–31.

    Article  CAS  PubMed  Google Scholar 

  164. Klug M, van den Buuse M. An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice. Front Behav Neurosci. 2013;7:149.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  165. Hill RA, Klug M, Kiss Von Soly S, Binder MD, Hannan AJ, van den Buuse M. Sex-specific disruptions in spatial memory and anhedonia in a ‘two hit’ rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signalling. Hippocampus. 2014;24(10):1197–211.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Mental Health Research Institute, Parkville, VIC, Australia

    Maren Klug Ph.D., Rachel Hill Ph.D. & Maarten Van den Buuse Ph.D.

  2. Swinburne University of Technology, Hawthorn, VIC, Australia

    Maren Klug Ph.D.

  3. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia

    Rachel Hill Ph.D.

  4. School of Psychology and Public Health, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia

    Maarten Van den Buuse Ph.D.

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  1. Maren Klug Ph.D.
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  2. Rachel Hill Ph.D.
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  3. Maarten Van den Buuse Ph.D.
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Correspondence to Maarten Van den Buuse Ph.D. .

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  1. Guaymallen Mendoza, Argentina

    Pascual Ángel Gargiulo

  2. Member of the Council of the Institute of Neurobiology (Buenos Aires); Member of the Board of Certification, National Academy of Medicine (Argentina), Psychiatrist by University Complutense of Madrid and University of Buenos Aires; Former Director of National Institute of Mental Health (Argentina), Cuyo, Buenos Aires, Argentina

    Humberto Luis Mesones Arroyo

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Klug, M., Hill, R., Van den Buuse, M. (2015). ‘Two Hit’ Neurodevelopmental Mechanisms in Schizophrenia: Focus on Animal Models and the Role of BDNF. In: Gargiulo, P., Arroyo, H. (eds) Psychiatry and Neuroscience Update. Springer, Cham. https://doi.org/10.1007/978-3-319-17103-6_24

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