The role and effects of maternal inflammation, environmental factors and epigenetics in childhood neurodevelopmental disorders

Abstract

Environmental exposures throughout life have significant impacts on child brain development. Human epidemiological studies support the link between maternal immune activation (MIA), via maternal inflammatory exposures during pregnancy, and development of neurodevelopmental disorders (NDD) in offspring. The current pathophysiological understanding of MIA includes disruptions in placental signaling, brain-immune signaling, and microglial activation, mediated by immune and epigenetic mechanisms. The Toll-like receptor pathway, a key innate immune pathway, is highlighted as a convergent link between MIA and offspring NDDs. Addressing the need for a comprehensive survey to examine environmental exposures in a child’s life, the GxE (gene x environment) survey was developed. Next, Paediatric Acute Neuropsychiatric Syndrome (PANS), characterised by abrupt onset obsessive compulsive disorder and neurodevelopmental regression triggered by infection or stress, was chosen as a model to further explore immune-brain interactions. Whether PANS is a distinct entity or part of a neurodevelopmental spectrum is uncertain. Children with PANS and non-PANS NDDs have higher reported early childhood infections and loss of previously acquired developmental skills compared to controls. Children with PANS have normal routine immune testing, however bulk RNA-sequencing revealed upregulated pathways in ribosomal biogenesis and RNA methyltransferases, and downregulated pathways in diverse cellular functions and immune responses. Single-cell RNA-sequencing confirmed these findings but showed heterogeneity across immune cell types. The clinical and biological data proposes PANS as an “epigenetic immune-brain dysregulation disorder”. Given the central role of the immune system in synaptic pruning and neurodevelopment, these insights provide rationale for novel epigenetic and immune modulating therapies to optimize neurodevelopmental trajectories and minimize neuropsychiatric impairment in NDDs.