INNATE IMMUNITY AND AUTISM IN CHILDREN BORN PRETERM

Risk of infection and autism spectrum disorders (ASD) is increased in preterm infants, particularly in boys.

However, while neonatal immune activation (NIA) has emerged as an important driving force in ASD, conclusive evidence for aetiology and pathogenesis has yet to be established and treatments are lacking.

The overall hypothesis is that modulation of Toll-like receptor (TLR)-signalling in the blood-brain barrier following NIA will prevent sex-dependent regulation of genes and proteins in microglia and ASD phenotype in males.

The specific aims are, in male and female mice, to determine: i) neuronal synaptic circuit remodelling and maturation, microglia-specific morphological and molecular modifications and ASD-like behaviour following NIA ii) TLR-dependent transcriptome profile in the cerebral vasculature following NIA iii) whether inhibition of TLR-signalling in the brain vasculature can halt development of ASD phenotype following NIA iv) whether maternal n-3 PUFA diet can protect cerebral vasculature and prevent ASD phenotype following NIA By combining in vivo conditional transgenic mice, cell-specific molecular profiling and state-of-the art multi-scale microscopy techniques with n-3 PUFA in age-appropriate animal models, we will uncover novel signalling pathways that impact on ASD.

Studying both males and females will allow discrimination between injurious and protective mechanisms and our results may contribute to more individually tailored therapies in the future.