Interferon-gamma signalling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

Abstract Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFNγ), in offspring’s brains play a central role. IFNγ activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFNγ has also been implicated in brain development. Here, we test the hypothesis that IFNγ signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We found that transient IFNγ treatment of neural progenitors derived from human induced pluripotent stem cells (hiPSCs) increased neurite outgrowth. RNA-sequencing analysis revealed that MHC class I (MHCI) genes were persistently upregulated through neuronal differentiation; an effect that was mediated by IFNγ-induced PML nuclear bodies. Critically, IFNγ-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFNγ disproportionately alters the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data indicate that IFNγ signalling may contribute to neurodevelopmental disorder aetiology.