title: 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.
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.
authors.affiliation: Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN 55455, USA. fatem002@umn.edu
authors.forename: S Hossein
authors.initials: SH
authors.lastname: Fatemi
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Folsom
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rooney
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.forename: Tess E
authors.initials: TE
authors.lastname: Kornfield
authors.forename: Teri J
authors.initials: TJ
authors.lastname: Reutiman
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kneeland
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Liesch
authors.forename: Kegang
authors.initials: K
authors.lastname: Hua
authors.forename: John
authors.initials: J
authors.lastname: Hsu
authors.forename: Divyen H
authors.initials: DH
authors.lastname: Patel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology / Q000821:virology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015967:Gene Expression Regulation, Viral; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000473:pathology; D010920:Placenta / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011247:Pregnancy; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology