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Prenatal human influenza viral infection and brain disorder in mouse: Relevance for genesis of schizophrenia

Fatemi, Hossein S. and Folsom, T. D. and Reutiman, T. J. and Mori, S. and Rooney, R. J. and Winter, C. and Smee, D. F. and Kornfield, T. E. and Patterson, P. (2013) Prenatal human influenza viral infection and brain disorder in mouse: Relevance for genesis of schizophrenia. Neurotoxicology and Teratology, 37 . p. 76. ISSN 0892-0362. http://resolver.caltech.edu/CaltechAUTHORS:20130730-110801932

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Abstract

Introduction: Schizophrenia is a severe neurodevelopmental disorder with a lifetime prevalence of 1%. Maternal viral infection is known to increase the risk for schizophrenia in the offspring. Methods: Our laboratory has developed a mouse model of prenatal viral infection in which C57BL/6 and Balb/c mice have been infected with a mouse-adapted influenza virus [A/WSN/33 strain (H1N1)] at specific dates during pregnancy: embryonic day 7 (E7), E9, E16, and E18. Pregnant dams were allowed to give birth and brains were collected from offspring at postnatal (P) day zero (P0), P14, P35, and P56. At each postnatal time point we evaluated brain morphology, mRNA, and protein expression. We examined behavior of mice following infection at E9. Results: We observed altered volumes of specific brain regions including the ventricular system, cerebellum, neocortex and hippocampus following infection at E9, E16 or E18 as well as changes in volume of gray and white matter. While infection at E7 had no effect on brain, there were deleterious effects on structure of the placenta on infected dams. Microarray experiments revealed brain gene expression changes that varied by infection date with 78 genes altered following infection at E7, 389 genes at E9, 2244 genes at E16, and 742 genes at E18. A number of important genes related to schizophrenia were among the altered genes including Mbp, Rgs4, Gad2, and Foxp2. qRT-PCR and western blotting verified change of direction for a number of these genes. Neurotransmitters were also altered following infection at E16 (reduced levels of serotonin) and E18 (reduced levels of serotonin, taurine, and 5-Hydroxyindoleacetic acid). Finally, following infection at E9, offspring behavioral deficits similar to what is observed in subjects with schizophrenia. These deficits were corrected using antipsychotic medications. Discussion: This model has 1) face validity in that both our model and patients with schizophrenia display deficits in PPI; 2) construct validity with similar decreased hippocampal and total brain volume, and alteration expression of numerous schizophrenia candidate genes; and 3) predictive validity in that administration of anti-psychotics that ameliorate PPI deficits in schizophrenics, corrected the PPI deficits in two strains of exposed mice. Grant support by NIH.


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http://dx.doi.org/10.1016/j.ntt.2013.03.012DOIAbstract
http://www.sciencedirect.com/science/article/pii/S0892036213000676PublisherAbstract
Additional Information:© 2013 Published by Elsevier Inc. Grant support by NIH.
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Record Number:CaltechAUTHORS:20130730-110801932
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20130730-110801932
Official Citation:S. Hossein Fatemi, T.D. Folsom, T.J. Reutiman, S. Mori, R.J. Rooney, C. Winter, D.F. Smee, T.E. Kornfield, P. Patterson, Prenatal human influenza viral infection and brain disorder in mouse: Relevance for genesis of schizophrenia, Neurotoxicology and Teratology, Volume 37, May–June 2013, Page 76, ISSN 0892-0362, http://dx.doi.org/10.1016/j.ntt.2013.03.012. (http://www.sciencedirect.com/science/article/pii/S0892036213000676)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39655
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:30 Jul 2013 18:32
Last Modified:07 Nov 2013 19:50

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