Elevated prenatal IL-6 levels disrupt early patterns of hippocampal electrical activity and chloride homeostasis by targeting GABAergic signaling at perinatal stage

Early patterns of neuronal electrical activity are fundamental for driving critical developmental processes, including neuronal maturation and synapse formation. While genetic programs are key in orchestrating these events, the influence of environmental stressors remains poorly defined. Maternal immune activation (MIA) during pregnancy induces a systemic cytokine surge that can profoundly impact fetal brain development, increasing the risk of psychiatric and neurodevelopmental disorders.

Here, we show that maternal elevation of interleukin-6 (IL-6) – a key cytokine upregulated during MIA – perturbs early hippocampal electrical activity in male offspring during the first postnatal week, a critical window for circuit formation. By triggering a STAT3-dependent modulation of early GABAergic synaptic transmission, IL-6 disrupts chloride homeostasis, causing a premature shift in the developmental GABA polarity switch. Our findings reveal a direct link between maternal immune signaling and early GABA-driven network maturation, providing insights into how inflammatory events during pregnancy may predispose male offspring to neurodevelopmental disorders.

We thank Alessandro Maccione from 3Brain for technical assistance and data analysis support during MEA recordings. The present study was supported by: PRIN-2022 Cod. 2022JLA3EA, PRIN-PNRR Cod. P2022LR49L and PNRR-CN00000041.

G.D. was supported by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. Institute of Neuroscience (IN-CNR), Consiglio Nazionale delle Ricerche, 20854, Vedano al Lambro, Italy IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy Genni Desiato, Edoardo Fraviga, Thomas Cassani, Riccardo Grassi, Martina Vitali, Francesca Fanuele, Federica Ruggeri, Marco Cremonesi, Marinos Kallikourdis, Michela Matteoli, Sebastiano Bariselli & Davide Pozzi Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy Edoardo Fraviga, Francesca Fanuele, Federica Ruggeri, Riccardo Fesce, Marinos Kallikourdis, Michela Matteoli, Sebastiano Bariselli & Davide Pozzi Centre de Recherche Azrieli, CHU Sainte-Justine/Université de Montréal, Montréal (Québec), QC, Canada Clara A. Amegandjin & Graziella Di Cristo Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, Genova, Italy The authors declare no competing interests.

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If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Desiato, G., Fraviga, E., Cassani, T. et al.