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-6R_) in placental trophoblasts (Cyp19-Cre^(+);Il6ra^(fl/fl)), and tested offspring of Cyp19-Cre^(+);Il6ra^(fl/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^(+);Il6ra^(fl/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.
Additional Information
© 2016 Elsevier. Received 27 July 2016; revised 20 October 2016; accepted 8 November 2016; available online 9 November 2016. We acknowledge H. Chu, A. Khoshnan, B.D. Needham, T.R. Sampson, C.E. Schretter, and G. Sharon for critically reviewing the manuscript; Professor Gustavo Leone for providing the Cyp19-Cre mouse line; Professor D.J. Anderson for providing ROSA::LSLlacZ mice; Professor A.J. Varshavsky for providing Ate1^(-/-) mouse; Professor J.M. Allman for use of the LCM equipment; Professor B.J. Wold for use of a cryostat; Dr. B. Williams for training and use of LCM and cryostat equipment; Dr. A. Collazo and Caltech Biological Imaging Center for the training and use of confocal microscope; L. Rodriguez for administrative assistance; J. Gutierrez, K.F. Lee, J. Rodriguez, L.C. Sandoval, N.A. Verduzco for caring of animals. This work was supported by NIH Conte Center Award (NIH 5P50MH086383-04, to P.H.P.); Autism Speaks (#7670, to P.H.P); postdoctoral fellowship from National Science Council, Taiwan (NSC 101-2917-I-564-039, to W.-L.W.); Autism Speaks Weatherstone Predoctoral Fellowship (to E.Y.H.) and NIH/NRSA Predoctoral Fellowship (to E.Y.H.); Caltech Undergraduate Research Fellowship (SURF) (to Z.Y.) and Amgen Scholars Program at Caltech (to Z.Y.); the Heritage Medical Research Institute (to S.K.M.), Simons Foundation (to S.K.M.), and NIH (MH100556 to S.K.M.).Attached Files
Accepted Version - nihms834429.pdf
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Additional details
- PMCID
- PMC5373986
- Eprint ID
- 71999
- DOI
- 10.1016/j.bbi.2016.11.007
- Resolver ID
- CaltechAUTHORS:20161114-135126065
- 5P50MH086383-04
- NIH
- 7670
- Autism Speaks
- NSC 101-2917-I-564-039
- National Science Council (Taipei)
- NIH Predoctoral Fellowship
- Caltech Summer Undergraduate Research Fellowship (SURF)
- AmGen Scholars Program
- Heritage Medical Research Institute
- Simons Foundation
- MH100556
- NIH
- Created
-
2016-11-15Created from EPrint's datestamp field
- Updated
-
2022-04-11Created from EPrint's last_modified field
- Caltech groups
- Heritage Medical Research Institute