Effects of prenatal maternal immune activation and exposure to circadian disruption during adolescence: exploring the two-hit model of neurodevelopmental disorders

Background: Around 80% of individuals with neurodevelopmental disorders (NDDs) such as schizophrenia and autism spectrum disorders experience disruptions in sleep/circadian rhythms. We explored whether prenatal infection, an established risk factor for NDDs, and environmental circadian disruption synergistically induced sex-specific deficits in mice. Methods: A maternal immune activation (MIA) protocol was used by injecting pregnant mice with a viral mimic poly IC (9.5) or saline. Then, juvenile/adolescent offspring (3-7 weeks old) were subjected to either standard lighting (12:12LD) or constant light (LL). Results: We found interactions of the two factors on behaviors related to cognition, anxiety, and sociability. Notably, poly IC exposure led to a more activated profile of hippocampal microglia in males only, while LL diminished these effects. Using RNA sequencing in the dorsal hippocampus, we found that poly IC exposure led to several differentially expressed genes in males (but not females), and fewer differential expressed genes were observed after LL exposure in both sexes. Using the WGCNA analysis, we found that modules of co-expressed genes associated with LL were enriched for pathways involved in synaptic transmission and vesicle mediated transport. Not only were many of these genes related to sleep/circadian rhythms and NDDs in humans, but they were also related to neurotransmission, suggesting that LL exerts its effects by disrupting the expression of proteins required for efficient neurotransmitter release. Conclusions: Understanding the link between circadian disruption and MIA is crucial for NDD due to the widespread exposure to environmental circadian disruption in society and the high transmission of viral infections among pregnant individuals.