Interferon-ɣ Exposure of Human iPSC-derived Neurons Alters Major Histocompatibility Complex I and Synapsin I Protein Expression
Human epidemiological data links maternal immune activation during gestation with increased risk for neurodevelopmental disorders including schizophrenia. Animal models of maternal immune activation (MIA) provide causal evidence for this association and strongly suggest that inflammatory cytokines act is a critical link between maternal infection and aberrant offspring brain and behavior development. This includes evidence for reduced synapse formation, consistent with post-mortem and in vivo evidence of reduced synaptic density in schizophrenia. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. Using a human cellular model, we recently demonstrated that acute exposure to interferon-ɣ (IFNɣ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNɣ affects synapse formation in an induced neuron model that generates forebrain glutamatergic neurons. Using immunocytochemistry and quantitative PCR, we demonstrate that acute IFNɣ exposure results in significantly increased MHCI expression at the mRNA and protein level. Furthermore, acute IFNɣ exposure decreases synapsin I protein in neurons but does not affect synaptic gene mRNA levels. Interestingly, complement component 4A (C4A) mRNA is also significantly increased following acute IFNɣ exposure. This study builds on our previous work by showing that IFNɣ-mediated disruption of relevant synaptic proteins can occur at early stages of synapse formation, potentially contributing to neurodevelopmental disorder phenotypes such as schizophrenia.