Elevated prenatal IL-6 levels disrupt early patterns of hippocampal electrical activity and chloride homeostasis by targeting GABAergic signaling at perinatal stage
Abstract 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.
Authors
- Laura Cancedda (ORCID: https://orcid.org/0000-0003-0566-057X)
- David Andruszewski (ORCID: https://orcid.org/0000-0003-3645-1877)
- Marinos Kallikourdis (ORCID: https://orcid.org/0000-0001-9318-3368)
- Graziella Di Cristo (ORCID: https://orcid.org/0000-0003-4464-4994)
- Riccardo Fesce (ORCID: https://orcid.org/0000-0001-9473-896X)
- Michela Matteoli (ORCID: https://orcid.org/0000-0002-3569-7843)
- Edoardo Fraviga (ORCID: https://orcid.org/0000-0002-0139-4203)
- Sebastiano Bariselli (ORCID: https://orcid.org/0000-0003-3483-3169)
- Ilgiz A. Mufazalov (ORCID: https://orcid.org/0000-0001-9332-0131)
- M. Cremonesi (ORCID: https://orcid.org/0000-0002-8817-2186)
- Andrea Contestabile (ORCID: https://orcid.org/0000-0002-5417-4722)
- Riccardo Grassi (ORCID: https://orcid.org/0000-0002-9774-7156)
- Clara A. Amegandjin
- Genni Desiato (ORCID: https://orcid.org/0000-0001-5281-0097)
- Davide Pozzi (ORCID: https://orcid.org/0000-0001-6436-0556)
- Filippo Mirabella (ORCID: https://orcid.org/0000-0002-4312-1350)
- Federica Ruggeri
- Francesca Fanuele (ORCID: https://orcid.org/0009-0002-6547-6352)
- Martina Vitali (ORCID: https://orcid.org/0009-0003-0513-012X)
- Thomas Cassani
Institutions
- Humanitas University (IT)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Italian Institute of Technology (IT)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Neuroscience Institute (IT)
- Human Technopole (IT)
- IRCCS Humanitas Research Hospital (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-15
- DOI
- https://doi.org/10.1038/s41467-026-78479-9
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondazione Cariplo
- Ministero dell’Istruzione, dell’Università e della Ricerca
- NextGenerationEU