The viral theory of schizophrenia revisited

Abnormal placental gene expression and structural changes with lack of evidence for H1N1 viral presence in placentae of infected mice or brains of exposed offspring

S. Hossein Fatemi, Timothy D. Folsom, Robert Rooney, Susumu Mori, Tess E. Kornfield, Teri J. Reutiman, Rachel E. Kneeland, Stephanie B. Liesch, Kegang Hua, John Hsu, Divyen H. Patel

Research output: Contribution to journalArticle

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Abstract

Researchers have long noted an excess of patients with schizophrenia were born during the months of January and March. This winter birth effect has been hypothesized to result either from various causes such as vitamin D deficiency (McGrath, 1999; McGrath et al.; 2010), or from maternal infection during pregnancy. Infection with a number of viruses during pregnancy including influenza, and rubella are known to increase the risk of schizophrenia in the offspring (Brown, 2006). Animal models using influenza virus or Poly I:C, a viral mimic, have been able to replicate many of the brain morphological, genetic, and behavioral deficits of schizophrenia (Meyer et al.; 2006, 2008a, 2009; Bitanihirwe et al.; 2010; Meyer and Feldon, 2010; Short et al.; 2010). Using a murine model of prenatal viral infection, our laboratory has shown that viral infection on embryonic days 9, 16, and 18 leads to abnormal expression of brain genes and brain structural abnormalities in the exposed offspring (Fatemi et al.; 2005, 2008a,b, 2009a,b). The purpose of the current study was to examine gene expression and morphological changes in the placenta, hippocampus, and prefrontal cortex as a result of viral infection on embryonic day 7 of pregnancy. Pregnant mice were either infected with influenza virus [A/WSN/33 strain (H1N1)] or sham-infected with vehicle solution. At E16, placentas were harvested and prepared for either microarray analysis or for light microscopy. We observed significant, upregulation of 77 genes and significant downregulation of 93 genes in placentas. In brains of exposed offspring following E7 infection, there were changes in gene expression in prefrontal cortex (6 upregulated and 24 downregulated at P0; 5 upregulated and 14 downregulated at P56) and hippocampus (4 upregulated and 6 downregulated at P0; 6 upregulated and 13 downregulated at P56). QRT-PCR verified the direction and magnitude of change for a number of genes associated with hypoxia, inflammation, schizophrenia, and autism. Placentas from infected mice showed a number of morphological abnormalities including presence of thrombi and increased presence of immune cells. Additionally, we searched for presence of H1N1 viral-specific genes for M1/M2, NA, and NS1 in placentas of infected mice and brains of exposed offspring and found none. Our results demonstrate that prenatal viral infection disrupts structure and gene expression of the placenta, hippocampus, and prefrontal cortex potentially explaining deleterious effects in the exposed offspring without evidence for presence of viral RNAs in the target tissues. This article is part of a Special Issue entitled 'Schizophrenia'.

Original languageEnglish (US)
Pages (from-to)1290-1298
Number of pages9
JournalNeuropharmacology
Volume62
Issue number3
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

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Placenta
Schizophrenia
Virus Diseases
Down-Regulation
Gene Expression
Brain
Prefrontal Cortex
Hippocampus
Pregnancy
Infection
Genes
Behavioral Genetics
Poly I-C
Vitamin D Deficiency
Viral Genes
Rubella
Influenza A virus
Viral RNA
Microarray Analysis
Autistic Disorder

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

The viral theory of schizophrenia revisited : Abnormal placental gene expression and structural changes with lack of evidence for H1N1 viral presence in placentae of infected mice or brains of exposed offspring. / Fatemi, S. Hossein; Folsom, Timothy D.; Rooney, Robert; Mori, Susumu; Kornfield, Tess E.; Reutiman, Teri J.; Kneeland, Rachel E.; Liesch, Stephanie B.; Hua, Kegang; Hsu, John; Patel, Divyen H.

In: Neuropharmacology, Vol. 62, No. 3, 01.03.2012, p. 1290-1298.

Research output: Contribution to journalArticle

Fatemi, S. Hossein ; Folsom, Timothy D. ; Rooney, Robert ; Mori, Susumu ; Kornfield, Tess E. ; Reutiman, Teri J. ; Kneeland, Rachel E. ; Liesch, Stephanie B. ; Hua, Kegang ; Hsu, John ; Patel, Divyen H. / The viral theory of schizophrenia revisited : Abnormal placental gene expression and structural changes with lack of evidence for H1N1 viral presence in placentae of infected mice or brains of exposed offspring. In: Neuropharmacology. 2012 ; Vol. 62, No. 3. pp. 1290-1298.
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abstract = "Researchers have long noted an excess of patients with schizophrenia were born during the months of January and March. This winter birth effect has been hypothesized to result either from various causes such as vitamin D deficiency (McGrath, 1999; McGrath et al.; 2010), or from maternal infection during pregnancy. Infection with a number of viruses during pregnancy including influenza, and rubella are known to increase the risk of schizophrenia in the offspring (Brown, 2006). Animal models using influenza virus or Poly I:C, a viral mimic, have been able to replicate many of the brain morphological, genetic, and behavioral deficits of schizophrenia (Meyer et al.; 2006, 2008a, 2009; Bitanihirwe et al.; 2010; Meyer and Feldon, 2010; Short et al.; 2010). Using a murine model of prenatal viral infection, our laboratory has shown that viral infection on embryonic days 9, 16, and 18 leads to abnormal expression of brain genes and brain structural abnormalities in the exposed offspring (Fatemi et al.; 2005, 2008a,b, 2009a,b). The purpose of the current study was to examine gene expression and morphological changes in the placenta, hippocampus, and prefrontal cortex as a result of viral infection on embryonic day 7 of pregnancy. Pregnant mice were either infected with influenza virus [A/WSN/33 strain (H1N1)] or sham-infected with vehicle solution. At E16, placentas were harvested and prepared for either microarray analysis or for light microscopy. We observed significant, upregulation of 77 genes and significant downregulation of 93 genes in placentas. In brains of exposed offspring following E7 infection, there were changes in gene expression in prefrontal cortex (6 upregulated and 24 downregulated at P0; 5 upregulated and 14 downregulated at P56) and hippocampus (4 upregulated and 6 downregulated at P0; 6 upregulated and 13 downregulated at P56). QRT-PCR verified the direction and magnitude of change for a number of genes associated with hypoxia, inflammation, schizophrenia, and autism. Placentas from infected mice showed a number of morphological abnormalities including presence of thrombi and increased presence of immune cells. Additionally, we searched for presence of H1N1 viral-specific genes for M1/M2, NA, and NS1 in placentas of infected mice and brains of exposed offspring and found none. Our results demonstrate that prenatal viral infection disrupts structure and gene expression of the placenta, hippocampus, and prefrontal cortex potentially explaining deleterious effects in the exposed offspring without evidence for presence of viral RNAs in the target tissues. This article is part of a Special Issue entitled 'Schizophrenia'.",
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