title: Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders.
abstract: Prenatal viral infection has been associated with development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) administration of influenza virus. We hypothesized that late second trimester infection (E18) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6J mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offsping of the infected mice were collected at P0, P14, P35 and P56, their brains removed and prefrontal cortex, hippocampus and cerebellum dissected and flash frozen. Microarray, qRT-PCR, DTI and MRI scanning, western blotting and neurochemical analysis were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with schizophrenia or autism including Sema3a, Trfr2 and Vldlr were found to be altered as were protein levels of Foxp2. E18 infection of C57BL6J mice with a sublethal dose of human influenza virus led to significant gene alterations in frontal, hippocampal and cerebellar cortices of developing mouse progeny. Brain imaging revealed significant atrophy in several brain areas and white matter thinning in corpus callosum. Finally, neurochemical analysis revealed significantly altered levels of serotonin (P14, P35), 5-Hydroxyindoleacetic acid (P14) and taurine (P35). We propose that maternal infection in mouse provides an heuristic animal model for studying the environmental contributions to genesis of schizophrenia and autism, two important examples of neurodevelopmental disorders.
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: Teri J
authors.initials: TJ
authors.lastname: Reutiman
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Folsom
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Kenichi
authors.initials: K
authors.lastname: Oishi
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
authors.forename: Christine
authors.initials: C
authors.lastname: Winter
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sohr
authors.forename: Georg
authors.initials: G
authors.lastname: Juckel
mesh_terms: D000818:Animals; D001284:Atrophy; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D005865:Gestational Age; D006801:Humans; D007091:Image Processing, Computer-Assisted; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011973:Receptors, LDL / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D040121:Semaphorin-3A / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; D018377:Neurotransmitter Agents; D011973:Receptors, LDL; D011990:Receptors, Transferrin; D012097:Repressor Proteins; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; C503641:TFR2 protein, mouse; C036053:VLDL receptor