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Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring.

Authors
  • Mirabella, Filippo1
  • Desiato, Genni2
  • Mancinelli, Sara3
  • Fossati, Giuliana3
  • Rasile, Marco4
  • Morini, Raffaella3
  • Markicevic, Marija5
  • Grimm, Christina5
  • Amegandjin, Clara6
  • Termanini, Alberto7
  • Peano, Clelia8
  • Kunderfranco, Paolo7
  • di Cristo, Graziella6
  • Zerbi, Valerio9
  • Menna, Elisabetta2
  • Lodato, Simona1
  • Matteoli, Michela10
  • Pozzi, Davide11
  • 1 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy. , (Italy)
  • 2 IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Neuroscience - National Research Council, 20139 Milan, Italy. , (Italy)
  • 3 IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy. , (Italy)
  • 4 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy. , (Italy)
  • 5 Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich 8057, Switzerland. , (Switzerland)
  • 6 Department of Neurosciences, Université de Montréal, Montréal, QC, Canada; CHU Sainte-Justine Research Center, Montréal, QC, Canada. , (Canada)
  • 7 Bioinformatic Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. , (Italy)
  • 8 Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, 20089 Rozzano, Milan, Italy; Genomic Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. , (Italy)
  • 9 Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich 8057, Switzerland; Neural Control of Movement Lab, Department of Health Sciences and Technology, ETH Zürich, Zürich 8057, Switzerland. , (Switzerland)
  • 10 IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Neuroscience - National Research Council, 20139 Milan, Italy. Electronic address: [email protected] , (Italy)
  • 11 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Immunity
Publication Date
Nov 09, 2021
Volume
54
Issue
11
Identifiers
DOI: 10.1016/j.immuni.2021.10.006
PMID: 34758338
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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