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Brain Behav Immun. 2017 May;62:11-23. doi: 10.1016/j.bbi.2016.11.007. Epub 2016 Nov 9.

The placental interleukin-6 signaling controls fetal brain development and behavior.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: wlwu@caltech.edu.
2
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.
3
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.
4
Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.
5
Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: php@caltech.edu.

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/fl mothers 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/fl offspring. 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.

KEYWORDS:

Autism spectrum disorder (ASD); Hindbrain development; Interleukin-6 (IL-6); Maternal immune activation (MIA); Maternal-placental-fetal axis; Placenta; Purkinje cells

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