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Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Smith, Stephen E. P. and Li, Jennifer and Garbett, Krassimira A. and Mirnics, Károly and Patterson, Paul H. (2007) Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6. Journal of Neuroscience, 27 (40). pp. 10695-10702. ISSN 0270-6474. PMCID PMC2387067.

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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.

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Additional Information:© 2007 Society for Neuroscience. For the first six months after publication SfN’s license will be exclusive. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license ( Received May 11, 2007; revised Aug. 14, 2007; accepted Aug. 18, 2007. This work was supported by the National Institute of Mental Health (K.M., P.H.P.) and the McKnight, Cure Autism Now, and Autism Speaks Foundations (P.H.P.). We thank Benjamin Deverman, Natalia Malkova, Limin Shi, Ali Khoshnan, and Lorena Sandoval for assistance and advice; Kathleen Hamilton for administrative support; and Amanda Miles for skillful technical assistance with the microarray experiments. Ben Deverman and Joanna Jankowsky also provided useful comments on this manuscript.
Funding AgencyGrant Number
National Institute of Mental Health (NIMH)UNSPECIFIED
McKnight FoundationUNSPECIFIED
Cure Autism Now FoundationUNSPECIFIED
Autism Speaks FoundationUNSPECIFIED
Subject Keywords:schizophrenia; autism; cytokine; poly(I:C); maternal immune activation; IL-6; influenza
Issue or Number:40
PubMed Central ID:PMC2387067
Record Number:CaltechAUTHORS:20160212-084626453
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64454
Deposited By: Tony Diaz
Deposited On:19 Feb 2016 20:57
Last Modified:03 Oct 2019 09:38

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