Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

By Stephen E P Smith, Jennifer Li, K. Garbett, K. Mirnics, P. Patterson. Journal of Neuroscience, 2007

1,564 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Immunology, Social Psychology

View Paper: https://www.semanticscholar.org/paper/9e21ef6c070a23a38b00fce4dad7521b29e10113

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Citations in the corpus

Conclusions about Interventions, Programs, and Approaches for Improving Executive Functions that appear Justified and those that, despite much hype, do not (2015, background): “…you are holding in mind or seeing how they relate to one another (‘working with’ the information you are holding in mind; Baddeley and Hitch, 1994; Smith and Jonides, 1999) and also for remembering your question or comment while following an ongoing discussion or for holding in mind what you…”
Early Life Programming and Neurodevelopmental Disorders (2010, background): “levels of cytokines such as IL-6 have been associated with deficits of several behaviors and neurophysiologic functions, including prepulse inhibition and latent inhibition (53).”
Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders (2010, background): “of maternal immune activation on fetal brain development ( Smith et al. 2007 ).”
The Central Nervous System and the Gut Microbiome (2016, background): “…behavior, social deficit, communication deficit IL-6 and IL-17A mediated behavioral and cortical development abnormalities; dysbiotic microbiome Smith et al., 2007; Choi et al., 2016 Propionic acid offspring exhibited anxiety-like behavior Foley et al., 2014 Postnatal Effects Perinatal Abx…”
Effects of prenatal infection on brain development and behavior: a review of findings from animal models. (2010, positive): “5 Mouse Smith et al. (2007) ; reversal learning of left–right discrimination; ; working memory in water maze; " AMPH- and MK801-induced locomotion (P98–P112) Poly IC, 5 mg/kg, iv E17 Mouse Meyer et al. (2006a, 2008c) ; spatial learning in Morris water maze (P140) IL-6, 9 lg/kg, ip E8, E10 and E12…”
Interleukin-6, a Major Cytokine in the Central Nervous System (2012, background): “Thus, a single maternal injection of IL-6 during pregnancy causes schizophrenia-like behavioral abnormalities in WT mice but not in IL-6 KO mice [227].”
The microbiota modulates gut physiology and behavioral abnormalities associated with autism (2013, neutral): “ameliorate MIA-associated increases in colon IL-6 is interesting as this cytokine is required for the development of behavioral deficits in MIA offspring (Smith et al., 2007).”
Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism (2012, methodology): “S1) that we have seen in single-injected mothers and influenza-infected mothers (Shi et al., 2003; Smith et al., 2007; Hsiao and Patterson, 2011).”
Immune involvement in schizophrenia and autism: etiology, pathology and animal models. (2009, positive): “Poly(I:C) acts through the toll-like receptor (TLR)3, and its injection in pregnant rats or mice is sufficient to cause all of the behavioral and histological abnormalities assayed for thus far in the offspring of maternal influenza infected mothers [31,35,42].”
The role of immune dysfunction in the pathophysiology of autism (2011, neutral): “In all four versions of the model, IL-6 appears to play an essential role and exposure to IL-6 alone during gestation is sufficient to elicit behavioral changes in the offspring (Hsiao and Patterson, 2011; Smith et al., 2007).”
Interneuron dysfunction in psychiatric disorders (2012, background): “For instance, maternal interleukin-6 production during infection impairs the balance of cytokines at perinatal stages and causes behavioural defects in offsprin”