Inflammation-induced neuro-epigenetic mechanisms of resilience and susceptibility to maternal immune activation

Neurodevelopmental disorders, such as schizophrenia, present a significant burden for the individual and society, and are caused by multiple genetic and environmental risk factors. A main risk factor predisposing individuals to develop such conditions is fetal exposure to maternal inflammation during a critical period of gestation. Yet, not all individuals exposed to maternal infection in utero will develop symptoms of neurodevelopmental disorders later in life.

Our proposal seeks to take a significant step in answering why some individuals are resilient and others are susceptible, and what the differences are in biological mechanisms that underpin the fetal response to maternal inflammation.

We predict that the answer is linked to individual differences in their response to specific proteins, referred to as cytokines, produced by mothers during an infection. The first step to an answer is to establish what distinguishes resilient and susceptible individuals in the mechanisms of their brain development. Our overall hypothesis is that cytokines produced in the fetal brain of offspring born to infected mothers during gestation modifies the regulation of gene expression in the fetal brain.

This, then, leads to altered brain development and ultimately dysfunctional behaviour in susceptible individuals.

To test our hypothesis we use a multidisciplinary approach of genomic, behavioural and cell-based technologies in a rat model that allows us to distinguish resilient and susceptible individuals, and to identify changes in the molecular mechanisms that regulate expression of genes (that is, epigenetic mechanisms) for brain development when exposed to maternal cytokines before birth. We are then able to establish which changes in these epigenetic mechanisms lead to symptoms of neurodevelopmental disorders during adolescence.

We are particularly interested in being able to identify resilient and susceptible individuals before they develop behavioural symptoms. To achieve this, we will measure a set of biomarkers of inflammation in the blood throughout development and link this to behaviour measured later in life.

Finally, we need to demonstrate that the differences between resilient and susceptible individuals are caused by exposure to elevated cytokines and lead to altered epigenetic profiles that ultimately change neuro- and brain development. Here, we will use neuroprogenitor cells and investigate how their development into specific brain cells responds to different cytokines.

Our results will enable a step change in our understanding of why some individuals are at greater risk than others of developing neurodevelopmental dysfunction, and a better identification of those individuals before symptoms become apparent. Our results will open up both new broad and specific questions about the molecular mechanisms that underpin resilience and susceptibility, and why they lead to behavioural differences much later in life. laying the foundation for new avenues of future research.

In addition, by using blood and behavioural markers that can also be obtained from humans or other model systems our proposal promises also offers significant translational benefits to the clinic and other model systems