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Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic PolyI:C
Published on: March 25, 2016
Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in
Filippo Mirabella1, Genni Desiato2, Sara Mancinelli3
1Department 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.
Insights
Prenatal exposure to elevated interleukin-6 (IL-6) enhances brain connectivity and glutamatergic synapses in offspring. This molecular pathway, involving STAT3 and RGS4, may link early inflammation to neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Early prenatal inflammatory conditions are linked to neurodevelopmental disorders.
- Maternal interleukin-6 (IL-6) elevation during pregnancy is associated with abnormal offspring behavior, but the underlying synaptic mechanisms are unclear.
Purpose of the Study:
- To investigate whether elevated IL-6 during prenatal development alters synaptic development and brain connectivity.
- To elucidate the molecular pathways involved in IL-6-mediated effects on neurodevelopment.
Main Methods:
- Transient elevation of IL-6 in pregnant mice or developing embryos.
- Analysis of synaptic development and brain connectivity in offspring.
- Investigation of gene expression, including synaptogenesis-related genes, transcription factors (STAT3), and RGS4.
- Examination of the STAT3-RGS4 pathway during maternal immune activation (poly(I:C) model).
Main Results:
- IL-6 elevation enhanced glutamatergic synapses and led to long-lasting brain hyperconnectivity in offspring.
- IL-6 activated synaptogenesis gene programs in glutamatergic neurons.
- The STAT3 transcription factor and RGS4 gene expression were required for IL-6 effects.
- The STAT3-RGS4 pathway was activated in neonatal brains during maternal immune activation.
Conclusions:
- Prenatal IL-6 elevation is sufficient to induce lasting changes in glutamatergic synaptogenesis and brain connectivity.
- The STAT3-RGS4 pathway mediates the effects of IL-6 on synaptic development.
- These findings provide a mechanistic link between prenatal inflammation and neurodevelopmental disorders.
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.
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