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

Filippo Mirabella; Genni Desiato; Sara Mancinelli; Giuliana Fossati; Marco Rasile; Raffaella Morini; Marija Markicevic; Christina Grimm; Clara Amegandjin; Alberto Termanini; Clelia Peano; Paolo Kunderfranco; Graziella di Cristo; Valerio Zerbi; Elisabetta Menna; Simona Lodato; Michela Matteoli; Davide Pozzi

doi:10.1016/j.immuni.2021.10.006

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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.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 01/05/2022 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/34758338

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