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Year : 2019  |  Volume : 7  |  Issue : 1  |  Page : 41-49

Prenatal exposure and fetal programming of schizophrenia

Department of Physical Activity and Health Promotion, Faculty of Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy

Date of Web Publication13-Sep-2019

Correspondence Address:
Mr. Chidiebere Emmanuel Okechukwu
Physical Activity and Health Promotion Unit, Faculty of Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Roma, RM
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njecp.njecp_12_19

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Schizophrenia (SCZ) is a neurodevelopmental disorder, which results to cognitive dysfunction and memory decline. Maternal undernutrition during fetal development alters epigenomic programming, and this might result to SCZ in offspring later in life because of the disruption of fetal brain development and synaptogenesis. Maternal stress, exposure to teratogens and neurotoxic agent, hypoxia, and viral infection alters fetal neurodevelopmental mechanisms because of an increase in inflammatory proteins. Interleukin 8 and tumor necrosis factor released due to stress and infection increase the risk of offspring developing SCZ later in life. Having infections linked to Toxoplasma gondii, Chlamydia, and some pathogens seropositivity during pregnancy or the period preceding childbirth are high-risk factors for offspring to develop SCZ later in life. This review was conducted by extracting papers using key terms indicating Schizophrenia, fetal programming of neurodevelopmental disorders, maternal undernutrition, maternal immune activation, and genome-wide studies through PubMed, Science Direct, PsychINFO, Medline, Web of Science, and Google Scholar. Maternal Stress was found to induce hypermethylation resulting to poor expression of reelin, which causes a reduction in GABAergic neurons in animal models. In vivo animal experimentation indicated that poor maternal care, unfavorable environmental factors, and conditions produce aberrant deoxyribonucleic acid methylation patterns at various gene loci in the medial prefrontal cortex of the brain, thus altering and modifying the network of genes involved in mental activities. However, the epigenomic mechanisms behind the fetal programming of SCZ have not been fully understood; more facts could be unraveled in the future.

Keywords: Fetal exposures, maternal health, neuropsychiatric disorder, prenatal care, schizophrenia

How to cite this article:
Okechukwu CE. Prenatal exposure and fetal programming of schizophrenia. Niger J Exp Clin Biosci 2019;7:41-9

How to cite this URL:
Okechukwu CE. Prenatal exposure and fetal programming of schizophrenia. Niger J Exp Clin Biosci [serial online] 2019 [cited 2021 Oct 15];7:41-9. Available from: https://www.njecbonline.org/text.asp?2019/7/1/41/266833

  Introduction Top

Schizophrenia (SCZ) is a neurodevelopmental disorder which results to cognitive dysfunction and memory decline with severe neuropsychiatric implications. SCZ is more prevalent in men than in women. Maternal malnutrition during fetal development affects molecular signaling pathways and this might result to SCZ in offspring later in life because of the disruption of epigenetic processes, and this plays a role in the pathogenesis of SCZ.[1] Molecular dysregulation in SCZ affects the dopamine, N-methyl-D-aspartate, and gamma-aminobutyric acid (GABA) metabolic pathways modulated by epigenetic mechanisms.[2] With reference to genomics, SCZ is a disorder of aberrant gene transcription and regulation. Adults with SCZ show deficits in glutamate decarboxylase 1 (GAD1) ribonucleic acid (RNA) and protein levels in multiple areas of the cerebral cortex, which implies molecular and cellular defects in subtypes of GABAergic interneurons essential for cognition. GAD1 GABA synthesis enzyme is regulated by neuronal activity and matures in the prefrontal cortex prior to adolescence. Low cortical GAD1 RNA activity is associated with changes in the epigenetic structures of the promoter, thus affecting deoxyribonucleic acid (DNA) methylation patterns. Prenatal exposure to famine is a risk factor for developing SCZ in offspring. The findings from an experimental study analyzing gene expression and epigenetic modifications in the brain of the offspring of the RLP50 rat (a rat model of prenatal famine exposure), reveal that offspring of RLP50 shows disparity in neurotransmitters and olfactory-linked gene expression. The differentially expressed genes are related to synaptic function and transcription regulation in the hippocampus.[3] Two genes linked with cognitive impairment, methyl CpG binding protein 2 and facilitated glucose transporter member 1 (Slc2a1), exhibit significant downregulation and Slc2a1 is hypermethylated in the hippocampus.[3] Prenatal exposure to famine which results to fetal malnutrition leads to the reprogramming of postnatal brain gene expression and epigenetic modifications are associated with the reprogramming process.[4] In the central nervous system, regulatory RNA networks and epigenetic mechanisms are important for gene transcription modifications, which play an important role in long-term memory formation and cognition.[5] Molecular genomic studies showed that SCZ is linked to fetal energy metabolism dysregulation and decreased function, and this is one of the consequences of prenatal famine linked to the pathogenesis of SCZ.[6] Prenatal stress leads to prefrontal malfunction through epigenetic alterations of the reelin gene, a gene that regulates neuronal migration and positioning in the developing brain.[6] Maternal obesity predisposes the fetus to SCZ, offspring may develop SCZ later in life.[7]

Maternal stress, hypoxia, and infection alter fetal neurodevelopmental mechanisms as a result of an increase in inflammatory proteins, interleukin 8 (IL-8), and tumor necrosis factor released due to stress and infection, thus increasing the risk of SCZ later in life.[8],[9],[10],[11] Having infections linked to Toxoplasma gondii, Chlamydia, and some pathogens seropositivity during pregnancy or the period preceding childbirth are high-risk factors for the offspring to develop SCZ later in life.[12] Poorly treated viral infection of the brain suffered during childhood is linked to the pathogenesis of psychosis in adulthood.[13] Maternal stress has been associated with an increased risk of SCZ as a result of its association with reelin. Maternal stress induces hypermethylation resulting to poor expression of reelin, which causes a reduction in GABAergic neurons in animal models.[14] In vivo animal experimentation indicates that poor maternal care and unfavorable environmental factors and conditions produce aberrant DNA methylation patterns at various gene loci in the medial prefrontal cortex of the fetal brain, and these alters and modifies the network of genes involved in mental activities situated in regions connected to neurochemical pathways which regulates mental activities and this result to the fetal programming of SCZ and other neurodevelopmental disorders due to abnormal DNA methylation, nucleosome remodeling linked with genes that regulate DNA methylation and histone acetylation, histone modifications, and poor regulation of microRNAs (miRNAs). Prenatal stress during the first trimester of pregnancy may predispose an offspring to SCZ later in life.[15] Negative attitude, isolation, neglect, maltreatment, and maternal undernutrition as a result of having an unwanted pregnancy may be associated with the development of SCZ in offspring later in life.[16]

Medical illnesses and obstetric complications are also risk factors for the pathogenesis of mental illness in adulthood.[17] Exposure to infection during pregnancy significantly increased the risk of depression in the Swedish population.[18] Hunter et al., 2018,[19] suggested that smoking and prenatal smoke exposure may likely be an independent risk factor for the development of SCZ in offspring. There are complex epigenomic interactions between prenatal environmental factors and genetic influences in the pathogenesis of SCZ.[20] Prenatal exposures and poor maternal care are associated with the development of SCZ in offspring during adolescence or adulthood. Prenatal exposure to famine, maternal stress, maternal obesity, hypoxia, and infection alters fetal neuroembryological mechanisms, metabolic pathways, signaling pathways, and regulations, thus increasing the risk of offspring developing SCZ later in life. Proper antenatal care and medical attention are important during pregnancy in order to avoid fetal programmed mental illnesses which may manifest during early childhood, adolescence, or adulthood in offspring. Postnatal care and child's health and periodic medical checkup are very relevant in the primary prevention of SCZ. There is a need for further experimental and clinical studies on the association of prenatal exposures and poor maternal care with the development of SCZ in offspring later in life.

  Methods Top

Papers were extracted using key terms indicating schizophrenia, epigenomes, fetal programming of neurodevelopmental disorders, maternal undernutrition, maternal immune activation (MIA), maternal infections, maternal genomes, genome-wide studies, and developmental programming through PubMed, Science Direct, PsychINFO, Medline, Web of Science, and Google Scholar databases.

  Developmental Programming Processes Associated With Schizophrenia Top

Prenatal exposure and poor maternal care received during infancy are associated with the development of SCZ in offspring in early adolescence or adulthood. Prenatal exposure to famine, maternal stress, maternal obesity, hypoxia, and infection alters fetal neuroembryological mechanisms and signaling because of an increase in inflammatory proteins, thus increasing the risk of offspring developing SCZ later in life [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]. Poor maternal care during infancy can be a risk factor for developing SCZ and its associated mental illness in offspring, poorly treated viral infection of the brain suffered during childhood is linked to the pathogenesis of SCZ in adulthood. Maternal stress has been associated with an increased risk of SCZ as a result of its association with reelin. Maternal genomes undergo epigenetic reprogramming because of maternal undernutrition, stress, hypoxia, prenatal viral infections, drug abuse, and maternal deprivation due to war, famine, and social adversity. Prenatal stress dysregulates an enzyme known as 11 β-hydroxysteroid dehydrogenase type 2 that is responsible for converting cortisone into inactive metabolites through DNA methylation in the placenta and fetal brain. The transmission of DNA, phenotypes, and transcriptomes from parent to offspring is associated with fetal programming of SCZ. The placenta serves as a medium of interaction between the mother and fetus thus maternal infection interacts with the fetus leading to the deletion of IL-6 by the placenta preventing MIA which leads to an increase in C-X-C motif chemokine 10 (CXCL10) in the fetal brain causing a reduction in fetal brain vascular endothelial growth factor and basic fibroblast growth factor levels.[21] Preeclampsia is associated with the development of SCZ in offspring [22] because CXCL10 is a key mediator in preeclampsia and in the innate immune response to T. gondii, a parasite that causes an infection known as toxoplasmosis which dysregulates maternal immunity.[7],[23],[24],[25],[26] Apart from toxoplasmosis, prenatal infections such as herpes simplex, polio, rubella, and varicella-zoster virus play a role in the developmental programming of SCZ and other neurodevelopmental disorders which manifest in the offspring later in life.[27],[28],[29],[30],[31],[32] Deficiency of Vitamin D maybe a contributory factor to fetal programming of SCZ because Vitamin D deficiency during pregnancy is associated with inflammation within the placenta and maternal inflammation disrupts neurogenesis by inducing fetal cytokine production.[33] SCZ and bipolar disorder shares same developmental risk factors,[34] some studies advocate an increased risk of SCZ with advancing paternal age, which may be due to an inheritance of paternal gene factors through paternal imprinting.[35],[36] However, advanced research studies show that SCZ is associated with advanced maternal age.[37] Prenatal obesity maybe linked to the fetal programming of SCZ as a result of upregulation of pro-inflammatory cytokines, cytokines are altered in the maternal serum, which has been found to be elevated in schizophrenics.[38],[39],[40],[41] The single-nucleotide polymorphism (SNP)-CACNA1C polymorphism (rs2283291) and SNP rs4648635 loci are contributory epigenetic factors in the developmental programming of SCZ.[42],[43] The Dutch Hunger Winter and the Great Chinese Famine are evidence that maternal undernutrition increases the risk of fetal programmed SCZ in utero, and this is linked to folate deficiency induced by famine and de novo mutation.[44] Maternal abuse of substances that alters extrasynaptic dopamine may likely impair cognition in offspring. Cigarette smoking during pregnancy can lead to alteration in DNA methylation and expression of microRNA, smoking alters the developmental patterning of DNA methylation and gene expression, causing slow neuronal maturation and abnormality due to nicotine.[45] Prenatal exposure to Lead (II) ion (Pb2+) was found to increase the risk of SCZ in the offspring later in life, and frequent aspirin intake during pregnancy alters the fetal immune system by dysregulating prostaglandin metabolic pathway, and these are associated with the risk of SCZ in offspring.[46],[47],[48]
Figure 1: Gene-environment and biopsychosocial factors associated with fetal programming of schizophrenia

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Figure 2: Dysregulation of epigenetic mechanisms due to gene-environment interactions in utero

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Figure 3: Role of prenatal infection in the fetal programming of schizophrenia

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Figure 4: Role of Gram-negative bacteria lipopolysaccharide in the fetal programming of schizophrenia due to maternal Gram-negative bacterial infection

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Figure 5: Chromosome location and close gene implicated in the pathogenesis of schizophrenia

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Prenatal abnormalities caused by viral mimic polyinosinic-polycytidylic acid (Poly I: C) alters fetal brain cytokine expression and postnatal behaviors.[49],[50],[51],[52],[53],[54] Low maternal body mass index may likely be associated with SCZ.[55],[56] Season of birth have been linked to the fetal programming of SCZ because schizophrenics are mostly born during winter or spring, and there is higher risk of viral infections during this period.[57],[58] A child that was born in an urban area is at risk of developing SCZ due to high level of stress, environmental pollution, and infectious agents within the urban areas.[59],[60],[61],[62],[63],[64] A pregnant woman who lost her husband [65] or a teenage girl or lady that have an unwanted pregnancy contributes to the fetal programming of SCZ due to biopsychosocial factors.[66] Maternal depression [67] and pregnancy during the war [68] are examples of biopsychosocial factors that are associated with the developmental programming processes of SCZ. Fetal hypoxia was found to induce neuroarchitectural injury and abnormalities in gray matter and ventricular complex of the fetal brain.[69],[70] Disrupted in schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) proteins are implicated in the fetal programming of SCZ,[71],[72] DISC1 modulates neuronal migration, cell proliferation,[73] and synaptogenesis in the fetal cortex.[74] Poly I: C lead to loss of cognition and memory in adult offspring of DISC1 phenotype in mice,[75] and this is linked to decreased size of the amygdala, periaqueductal gray matter, number of dendritic spines in the hippocampus, and hyperactive of IL-6.[76] NRG-1, COMT, DNTBP1 PRODH, and RELN are linked to fetal hypoxia, and fetal hypoxia causes fetal inflammatory hyperactivity and fetal brain injury by upregulating inflammatory cytokine reactions.[77] Mutation of NRG1 may be linked to immune dysregulation in SCZ.[78] High level of kynurenic acid during fetal brain development may be linked to the pathogenesis of SCZ,[79],[80] because high plasma tryptophan and kynurenine levels in the developing brain is implicated in neurodegeneration.[81] Bacterial cell wall component from Gram-negative bacteria lipopolysaccharide administered to rats causes inflammation due to cytokine hyperactivity,[82] cognitive impairment,[83] memory loss,[84],[85] and decreased number of dendrites.[86],[87],[88] Research findings from a genome-wide study,[89] in which 230,000 cytosine nucleotide-guanine nucleotides (CpGs) was analyzed during fetal development, shows that 6480 methylated regions (DMRs) were isolated during the second fetal trimester to postnatal life transition phase, 4557 genes were further mapped. The genetic risk loci for SCZ contained 2903 CpGs; evidence showed that they methylated during the perinatal transition phase. This shows that aberrant DNA methylation patterning is associated with the development of SCZ, and this is the implication of fetal programming.

  Future Perspectives Top

There is need to perform a comparative investigation on the mechanisms and levels of DNA methylation among population samples of individuals who were born during famine, war, armed conflicts and are suffering from SCZ and those that were born during these periods but are free from neuropsychiatric disorders. Production of highly specific and potent proteomic biomarkers that can detect natal risk of SCZ and other neurodevelopmental diseases in utero are much needed in the prevention of fetal programmed SCZ and other neurodevelopmental disorders. There is a need for further studies on the role of intrauterine growth retardation (IUGR) proliferation and progression in the development of SCZ, by studying IUGR behaviors in pregnant rat models induced with stress or underfed. There is a need to understand the mechanisms of oxidative stress on the placenta and the counteracting effects of antioxidants. It is important to develop a potential therapy that can target miRNAs in the treatment of SCZ. Novel research on inflammatory responses, hormonal regulations, and the regulations of neurotransmitters such as dopamine, noradrenaline, serotonin, histamine, and GABA in animal models induced with infectious diseases and famine will play a key role in finding a more potential treatment of SCZ. Copy number variants (CNVs) are associated with increased risk of SCZ. CNVs can be analyzed during karyotyping amniocentesis, and this procedure is very important in the early detection of the possible development of SCZ or any other neurodevelopmental disorders in offspring later in life. There is a need for the application of stem cell technology and tissue engineering in the early prevention and treatment of SCZ. The association between gene expression and the pathogenesis of SCZ needs to be fully understood, and this will enable the development of molecular tools to correct the polygenic risks linked to SCZ.

  Conclusion Top

The pathogenesis of SCZ is associated with neurodevelopmental processes due to the alteration of normal epigenomic mechanisms such as genetic inheritance and gene-environment interactions. These alterations result to aberrant DNA methylation patterns at various gene loci in the medial prefrontal cortex of the fetal brain, thereby altering and modifying the network of genes involved in mental activities situated in the regions connected to neurochemical pathways which regulate mental activities, and this result to the fetal programming of SCZ. Gene-environment risk factors associated with SCZ are stress, hypoxia, maternal smoking, substance abuse, maternal exposure to organic pollutants, urban birth, exposure to teratogens, prenatal exposure to viral, Gram-negative bacterial and parasitic infections, gut microbiota, maternal undernutrition, drug abuse, and winter and spring birth. Biopsychosocial factors such as paternal age, maternal deprivation due to war and famine, social adversity, isolation, and unwanted pregnant are risk factors linked to the development of SCZ in offspring later in life. Regular and proper antenatal care is essential, in order to avoid genetic interactions with environmental risk factors, biopsychosocial risk factors, lifestyle behaviors, and teratogenic and neurotoxic agents that may alter fetal neurogenesis and brain development. The epigenomic mechanisms behind the fetal programming of SCZ have not been fully understood; however, more facts would likely be unraveled in the future.

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  References Top

Ibi D, González-Maeso J. Epigenetic signaling in schizophrenia. Cell Signal 2015;27:2131-6.  Back to cited text no. 1
Shorter KR, Miller BH. Epigenetic mechanisms in schizophrenia. Prog Biophys Mol Biol 2015;118:1-7.  Back to cited text no. 2
Xu J, He G, Zhu J, Zhou X, St. Clair D, Wang T, et al. Prenatal nutritional deficiency reprogrammed postnatal gene expression in mammal brains: Implications for schizophrenia. Int J Neuropsychopharmacol 2014;18. pii: pyu054.  Back to cited text no. 3
Butler AA, Webb WM, Lubin FD. Regulatory RNAs and control of epigenetic mechanisms: Expectations for cognition and cognitive dysfunction. Epigenomics 2016;8:135-51.  Back to cited text no. 4
MacDonald ML, Ding Y, Newman J, Hemby S, Penzes P, Lewis DA, et al. Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol Psychiatry 2015;77:959-68.  Back to cited text no. 5
Negrón-Oyarzo I, Lara-Vásquez A, Palacios-García I, Fuentealba P, Aboitiz F. Schizophrenia and reelin: A model based on prenatal stress to study epigenetics, brain development and behavior. Biol Res 2016;49:16.  Back to cited text no. 6
Brown AS. The environment and susceptibility to schizophrenia. Prog Neurobiol 2011;93:23-58.  Back to cited text no. 7
le Charpentier Y, Hoang C, Mokni M, Finet JF, Biaggi A, Saguin M, et al. Histopathology and ultrastructure of opportunistic infections of the digestive tract in acquired immunodeficiency syndrome. Arch Anat Cytol Pathol 1992;40:138-49.  Back to cited text no. 8
van Os J, Kapur S. Schizophrenia. Lancet 2009;374:635-45.  Back to cited text no. 9
Picchioni MM, Murray RM. Schizophrenia. BMJ 2007;335:91-5.  Back to cited text no. 10
Yolken R. Viruses and schizophrenia: A focus on herpes simplex virus. Herpes 2004;11 Suppl 2:83A-88A.  Back to cited text no. 11
Arias I, Sorlozano A, Villegas E, de Dios Luna J, McKenney K, Cervilla J, et al. Infectious agents associated with schizophrenia: A meta-analysis. Schizophr Res 2012;136:128-36.  Back to cited text no. 12
Fisher HL, Murphy TM, Arseneault L, Caspi A, Moffitt TE, Viana J, et al. Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms. Epigenetics 2015;10:1014-23.  Back to cited text no. 13
Bator E, Latusz J, Radaszkiewicz A, Wędzony K, Maćkowiak M. Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia. Pharmacol Rep 2015;67:1124-9.  Back to cited text no. 14
Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry 2008;65:146-52.  Back to cited text no. 15
Herman DB, Brown AS, Opler MG, Desai M, Malaspina D, Bresnahan M, et al. Does unwantedness of pregnancy predict schizophrenia in the offspring? Findings from a prospective birth cohort study. Soc Psychiatry Psychiatr Epidemiol 2006;41:605-10.  Back to cited text no. 16
Pugliese V, Bruni A, Carbone EA, Calabrò G, Cerminara G, Sampogna G, et al. Maternal stress, prenatal medical illnesses and obstetric complications: Risk factors for schizophrenia spectrum disorder, bipolar disorder and major depressive disorder. Psychiatry Res 2019;271:23-30.  Back to cited text no. 17
Al-Haddad BJ, Jacobsson B, Chabra S, Modzelewska D, Olson EM, Bernier R, et al. Long-term risk of neuropsychiatric disease after exposure to infection in utero. JAMA Psychiatry 2019;76:594-602.  Back to cited text no. 18
Hunter A, Murray R, Asher L, Leonardi-Bee J. The effects of tobacco smoking, and prenatal tobacco smoke exposure, on risk of schizophrenia: A systematic review and meta-analysis. Nicotine Tob Res 2018. doi: 10.1093/ntr/nty160. [Epub ahead of print].  Back to cited text no. 19
Davis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, et al. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci Biobehav Rev 2016;65:185-94.  Back to cited text no. 20
Wu WL, Hsiao EY, Yan Z, Mazmanian SK, Patterson PH. The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun 2017;62:11-23.  Back to cited text no. 21
Dachew BA, Mamun A, Maravilla JC, Alati R. Association between hypertensive disorders of pregnancy and the development of offspring mental and behavioural problems: A systematic review and meta-analysis. Psychiatry Res 2018;260:458-67.  Back to cited text no. 22
Gotsch F, Romero R, Friel L, Kusanovic JP, Espinoza J, Erez O, et al. CXCL10/IP-10: A missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern Fetal Neonatal Med 2007;20:777-92.  Back to cited text no. 23
Boij R, Svensson J, Nilsson-Ekdahl K, Sandholm K, Lindahl TL, Palonek E, et al. Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. Am J Reprod Immunol 2012;68:258-70.  Back to cited text no. 24
Khan IA, MacLean JA, Lee FS, Casciotti L, DeHaan E, Schwartzman JD, et al. IP-10 is critical for effector T cell trafficking and host survival in toxoplasma gondii infection. Immunity 2000;12:483-94.  Back to cited text no. 25
McGrath JJ, Féron FP, Burne TH, Mackay-Sim A, Eyles DW. The neurodevelopmental hypothesis of schizophrenia: A review of recent developments. Ann Med 2003;35:86-93.  Back to cited text no. 26
Debnath M, Venkatasubramanian G, Berk M. Fetal programming of Schizophrenia. Neurosci Biobehav Rev 2015;49:90-104.  Back to cited text no. 27
Brown AS, Cohen P, Harkavy-Friedman J, Babulas V, Malaspina D, Gorman JM, et al. A.E. Bennett research award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry 2001;49:473-86.  Back to cited text no. 28
Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001;58:1032-7.  Back to cited text no. 29
Torrey EF, Yolken RH. Could schizophrenia be a viral zoonosis transmitted from house cats? Schizophr Bull 1995;21:167-71.  Back to cited text no. 30
Brown AS. Prenatal infection and adult schizophrenia: A review and synthesis. Int J Ment Health 2001;29:22-37.  Back to cited text no. 31
Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004;61:774-80.  Back to cited text no. 32
Mendes-da-Silva C, Lemes SF, Baliani Tda S, Versutti MD, Torsoni MA. Increased expression of Hes5 protein in Notch signaling pathway in the hippocampus of mice offspring of dams fed a high-fat diet during pregnancy and suckling. Int J Dev Neurosci 2015;40:35-42.  Back to cited text no. 33
Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study. Lancet 2009;373:234-9.  Back to cited text no. 34
Malaspina D. Paternal factors and schizophrenia risk: De novo mutations and imprinting. Schizophr Bull 2001;27:379-93.  Back to cited text no. 35
Perrin MC, Brown AS, Malaspina D. Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull 2007;33:1270-3.  Back to cited text no. 36
Petersen L, Mortensen PB, Pedersen CB. Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry 2011;168:82-8.  Back to cited text no. 37
Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP, et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001;47:13-25.  Back to cited text no. 38
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review. Biol Psychiatry 2008;63:801-8.  Back to cited text no. 39
Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis. Schizophr Res 2014;155:101-8.  Back to cited text no. 40
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry 2011;70:663-71.  Back to cited text no. 41
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421-7.  Back to cited text no. 42
Numata S, Ye T, Herman M, Lipska BK. DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with Schizophrenia. Front Genet 2014;5:280.  Back to cited text no. 43
McClellan JM, Susser E, King MC. Maternal famine, de novo mutations, and schizophrenia. JAMA 2006;296:582-4.  Back to cited text no. 44
Thompson BL, Levitt P, Stanwood GD. Prenatal exposure to drugs: Effects on brain development and implications for policy and education. Nat Rev Neurosci 2009;10:303-12.  Back to cited text no. 45
Chang L, Alicata D, Ernst T, Volkow N. Structural and metabolic brain changes in the striatum associated with methamphetamine abuse. Addiction 2007;102 Suppl 1:16-32.  Back to cited text no. 46
Chang L, Smith LM, LoPresti C, Yonekura ML, Kuo J, Walot I, et al. Smaller subcortical volumes and cognitive deficits in children with prenatal methamphetamine exposure. Psychiatry Res 2004;132:95-106.  Back to cited text no. 47
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 2009;66:13-20.  Back to cited text no. 48
Meyer U, Knuesel I, Nyffeler M, Feldon J. Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis. Psychopharmacology (Berl) 2010;208:531-43.  Back to cited text no. 49
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;33:441-56.  Back to cited text no. 50
Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: A neurodevelopmental animal model of schizophrenia. Biol Psychiatry 2006;59:546-54.  Back to cited text no. 51
Zuckerman L, Weiner I. Post-pubertal emergence of disrupted latent inhibition following prenatal immune activation. Psychopharmacology (Berl) 2003;169:308-13.  Back to cited text no. 52
Zuckerman L, Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res 2005;39:311-23.  Back to cited text no. 53
Li Q, Cheung C, Wei R, Hui ES, Feldon J, Meyer U, et al. Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: Evidence from MRI in a mouse model. PLoS One 2009;4:e6354.  Back to cited text no. 54
Done DJ, Crow TJ, Johnstone EC, Sacker A. Childhood antecedents of schizophrenia and affective illness: Social adjustment at ages 7 and 11. BMJ 1994;309:699-703.  Back to cited text no. 55
Wahlbeck K, Forsén T, Osmond C, Barker DJ, Eriksson JG. Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Arch Gen Psychiatry 2001;58:48-52.  Back to cited text no. 56
Bradbury TN, Miller GA. Season of birth in schizophrenia: A review of evidence, methodology, and etiology. Psychol Bull 1985;98:569-94.  Back to cited text no. 57
Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: A review of the literature. Schizophr Res 1997;28:1-38.  Back to cited text no. 58
March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, et al. Psychosis and place. Epidemiol Rev 2008;30:84-100.  Back to cited text no. 59
Marcelis M, Navarro-Mateu F, Murray R, Selten JP, Van Os J. Urbanization and psychosis: A study of 1942-1978 birth cohorts in the Netherlands. Psychol Med 1998;28:871-9.  Back to cited text no. 60
Marcelis M, Takei N, van Os J. Urbanization and risk for schizophrenia: Does the effect operate before or around the time of illness onset? Psychol Med 1999;29:1197-203.  Back to cited text no. 61
Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry 2001;58:1039-46.  Back to cited text no. 62
Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol 2006;163:971-8.  Back to cited text no. 63
Krabbendam L, van Os J. Schizophrenia and urbanicity: A major environmental influence – Conditional on genetic risk. Schizophr Bull 2005;31:795-9.  Back to cited text no. 64
Huttunen MO, Niskanen P. Prenatal loss of father and psychiatric disorders. Arch Gen Psychiatry 1978;35:429-31.  Back to cited text no. 65
Myhrman A, Rantakallio P, Isohanni M, Jones P, Partanen U. Unwantedness of a pregnancy and schizophrenia in the child. Br J Psychiatry 1996;169:637-40.  Back to cited text no. 66
Van Erp TG, Saleh PA, Rosso IM, Huttunen M, Lönnqvist J, Pirkola T, et al. Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am J Psychiatry 2002;159:1514-20.  Back to cited text no. 67
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;155:355-64.  Back to cited text no. 68
Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: Historical and meta-analytic review. Am J Psychiatry 2002;159:1080-92.  Back to cited text no. 69
Cannon TD, van Erp TG, Rosso IM, Huttunen M, Lönnqvist J, Pirkola T, et al. Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 2002;59:35-41.  Back to cited text no. 70
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000;9:1415-23.  Back to cited text no. 71
Ishizuka K, Paek M, Kamiya A, Sawa A. A review of disrupted-in-schizophrenia-1 (DISC1): Neurodevelopment, cognition, and mental conditions. Biol Psychiatry 2006;59:1189-97.  Back to cited text no. 72
Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 2011;12:707-22.  Back to cited text no. 73
Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ, et al. Disrupted-in-schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via rac1. Nat Neurosci 2010;13:327-32.  Back to cited text no. 74
Nagai T, Kitahara Y, Ibi D, Nabeshima T, Sawa A, Yamada K. Effects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI: C treatment. Behav Brain Res 2011;225:305-10.  Back to cited text no. 75
Lipina TV, Zai C, Hlousek D, Roder JC, Wong AH. Maternal immune activation during gestation interacts with Disc1 point mutation to exacerbate schizophrenia-related behaviors in mice. J Neurosci 2013;33:7654-66.  Back to cited text no. 76
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;71:877-92.  Back to cited text no. 77
Marballi K, Quinones MP, Jimenez F, Escamilla MA, Raventós H, Soto-Bernardini MC, et al. In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation. J Mol Med (Berl) 2010;88:1133-41.  Back to cited text no. 78
Alexander KS, Pocivavsek A, Wu HQ, Pershing ML, Schwarcz R, Bruno JP. Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: Reversal with galantamine. Neuroscience 2013;238:19-28.  Back to cited text no. 79
Pocivavsek A, Wu HQ, Elmer GI, Bruno JP, Schwarcz R. Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur J Neurosci 2012;35:1605-12.  Back to cited text no. 80
Möller M, Du Preez JL, Emsley R, Harvey BH. Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment. Neuropharmacology 2012;62:2499-506.  Back to cited text no. 81
Boksa P. Effects of prenatal infection on brain development and behavior: A review of findings from animal models. Brain Behav Immun 2010;24:881-97.  Back to cited text no. 82
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;26:204-15.  Back to cited text no. 83
Coyle P, Tran N, Fung JN, Summers BL, Rofe AM. Maternal dietary zinc supplementation prevents aberrant behaviour in an object recognition task in mice offspring exposed to LPS in early pregnancy. Behav Brain Res 2009;197:210-8.  Back to cited text no. 84
Fortier ME, Joober R, Luheshi GN, Boksa P. Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring. J Psychiatr Res 2004;38:335-45.  Back to cited text no. 85
Baharnoori M, Brake WG, Srivastava LK. Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats. Schizophr Res 2009;107:99-109.  Back to cited text no. 86
Cui K, Ashdown H, Luheshi GN, Boksa P. Effects of prenatal immune activation on hippocampal neurogenesis in the rat. Schizophr Res 2009;113:288-97.  Back to cited text no. 87
Jenkins TA, Harte MK, Stenson G, Reynolds GP. Neonatal lipopolysaccharide induces pathological changes in parvalbumin immunoreactivity in the hippocampus of the rat. Behav Brain Res 2009;205:355-9.  Back to cited text no. 88
Jaffe AE, Gao Y, Deep-Soboslay A, Tao R, Hyde TM, Wienberger DR, et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat Neurosci 2016;19:40-7.  Back to cited text no. 89


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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