Maternal immune activation alters fetal brain development through interleukin-6.
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.
Smith
Stephen E P
SE
Biology Division, California Institute of Technology, Pasadena, California 91125, USA.
Li
Jennifer
J
Garbett
Krassimira
K
Mirnics
Karoly
K
Patterson
Paul H
PH
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001522:Behavior, Animal; D001921:Brain / Q000196:embryology* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D015850:Interleukin-6 / Q000172:deficiency / Q000502:physiology*; D007398:Interpersonal Relations; D008070:Lipopolysaccharides; D033261:Maternal-Fetal Relations; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011070:Poly I-C; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000276:immunology*
D000906:Antibodies; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011070:Poly I-C