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PMID: 17913903 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Maternal immune activation alters fetal brain development through interleukin-6.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 27 ·No. 40 ·2007-10-03 ·Pages 10695-702

Smith SE, Li J, Garbett K, Mirnics K, Patterson PH

Abstract

Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.

MeSH Terms
Analysis of Variance Animals Antibodies/administration & dosage Behavior, Animal Brain/embryology,immunology Cytokines/immunology,metabolism Embryo, Mammalian Enzyme-Linked Immunosorbent Assay/methods Exploratory Behavior Female Fetal Development/physiology Interleukin-6/deficiency,physiology Interpersonal Relations Lipopolysaccharides Maternal-Fetal Relations Mice Mice, Inbred C57BL Mice, Knockout Neural Inhibition/drug effects,physiology Oligonucleotide Array Sequence Analysis/methods Poly I-C Pregnancy Prenatal Exposure Delayed Effects/chemically induced,immunology
Chemicals
Antibodies Cytokines Interleukin-6 Lipopolysaccharides Poly I-C
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Smith Stephen E P
Biology Division, California Institute of Technology, Pasadena, California 91125, USA.
Li Jennifer
Garbett Krassimira
Mirnics Karoly
Patterson Paul H
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2178-07.2007
Published
2007-10-03
Pages
10695-702
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC2387067
Subset
IM
Grants
Autism Speaks · AS1606 · United States
NIMH NIH HHS · R01 MH067978 · United States
NIMH NIH HHS · R01 MH067978-04 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2178-07.2007 PMC Full Text View journal details
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