Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring

Immunity. 2021 Nov 9;54(11):2611-2631.e8. doi: 10.1016/j.immuni.2021.10.006.


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.

Keywords: IL-6; RGS4; STAT3; brain connectivity; glutamatergic transmission; maternal immune activation; neurodevelopmental disorder; neuroinflammation; pro-inflammatory cytokines; synaptic development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Disease Susceptibility
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology
  • Inflammation Mediators / metabolism
  • Interleukin-6 / biosynthesis*
  • Maternal Exposure*
  • Mice
  • Neurons / metabolism*
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Signal Transduction
  • Synapses / metabolism*
  • Synaptic Transmission


  • Cytokines
  • Inflammation Mediators
  • Interleukin-6