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.
10.1101/2020.11.02.364356 bioRxivShow 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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