Maternal immune activation (MIA) during pregnancy is a recognised environmental risk factor for psychiatric diseases, such as schizophrenia. MIA triggers various pathophysiological processes, including inflammation in the mother and the developing offspring. However, the precise molecular mechanisms through which MIA influences brain development are not well understood. 

To gain insights into the early impact of MIA on neurodevelopment, pregnant dams were injected with Poly (I:C), a mismatched double-stranded RNA mimicking viral infection, at embryonic day 9.5. To identify gene expression changes triggered by MIA, we performed RNA sequencing on embryonic brains at 3 hours (peak immune response) and 72 hours (response subsided) post-MIA.

Our results reveal significant changes in genes associated with proliferation and differentiation, alongside a marked reduction in Long Interspersed Element 1 (LINE-1) expression 3 hours post-MIA. LINE-1 is a repetitive, mobile DNA element that can affect gene expression, and its dysregulation has been previously linked to schizophrenia. Using Oxford Nanopore long-read DNA sequencing, we identified genome-wide increased LINE-1 methylation in MIA compared to controls. Further, LINE-1 protein expression was reduced in embryonic brains at 72 hours, a finding confirmed through an orthogonal approach in neuronal cultures. 

These observations are intriguing, as recent research (Toda et al., Cell Rep, 2024) suggests that LINE-1 may play a role in maintaining neural progenitor pools and regulating neuronal differentiation. Our ongoing work aims to determine whether LINE-1 downregulation persists at later stages in the MIA model, identify the specific epigenetic mechanisms at play, and understand its contribution to pathogenesis.