title: The placental interleukin-6 signaling controls fetal brain development and behavior.
abstract: Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/flmothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre+;Il6rafl/floffspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: wlwu@caltech.edu.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Wu
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA; Department of Integrative Biology & Physiology, University of California, Los Angeles, 610 Charles E. Young Drive, Los Angeles, CA 90095, USA. Electronic address: ehsiao@ucla.edu.
authors.forename: Elaine Y
authors.initials: EY
authors.lastname: Hsiao
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: Zihao_Yan@hms.harvard.edu.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.
authors.forename: Sarkis K
authors.initials: SK
authors.lastname: Mazmanian
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: php@caltech.edu.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6
keywords: Autism spectrum disorder (ASD); Hindbrain development; Interleukin-6 (IL-6); Maternal immune activation (MIA); Maternal-placental-fetal axis; Placenta; Purkinje cells