Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring

Mirabella, F.; Desiato, G.; Mancinelli, S.; Fossati, G.; Rasile, M.; Morini, R.; Markicevic, M.; Grimm, C.; amegandjin, C.; Termanini, A.; Peano, C.; Kunderfranco, P.; DiCristo, G.; Zerbi, V.; Lodato, S.; Menna, E.; Matteoli, M.; Pozzi, D.

doi:10.1101/2020.11.02.364356

bioRxiv · 10.1101/2020.11.02.364356

Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring

Mirabella, F.·Desiato, G.·Mancinelli, S.·Fossati, G.·Rasile, M.·Morini, R.·Markicevic, M.·Grimm, C.·amegandjin, C.·Termanini, A.·Peano, C.·Kunderfranco, P.·DiCristo, G.·Zerbi, V.·Lodato, S.·Menna, E.·Matteoli, M.·Pozzi, D.

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Abstract

Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuron-autonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

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Mirabella, F., Desiato, G., Mancinelli, S., Fossati, G., Rasile, M., Morini, R., Markicevic, M., Grimm, C., amegandjin, C., Termanini, A., Peano, C., Kunderfranco, P., DiCristo, G., Zerbi, V., Lodato, S., Menna, E., Matteoli, M., Pozzi, D.. 2020-11-02. Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring. https://doi.org/10.1101/2020.11.02.364356

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