Understanding the role of inflammation and epigenetics in neurodevelopmental and neuropsychiatric disorders

Abstract

Neurodevelopmental disorders (NDD) are heterogenous neurological conditions affecting brain development between the window of early gestation and early adulthood. Neurodevelopmental disorders encompass intellectual disability, Autism spectrum disorders (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and tic disorders such as Tourette syndrome, and neuropsychiatric conditions such as Obsessive-compulsive disorder (OCD). These conditions are highly comorbid, where individuals with one NDD often suffer from one or more NDD. Paediatric Acute Neuropsychiatric Syndrome (PANS) is a neurodevelopmental disorder phenotype, dominated by OCD and is often accompanied with ASD and tic symptoms. A large body of evidence support the involvement of maternal immune dysregulation during gestation as a risk factor for neurodevelopmental and neuropsychiatric conditions (Chapter 1), and the role of the immune system in NDDs more generally. This thesis aimed to investigate the immune and inflammatory dysregulations in individuals with NDDs. The first study utilised publicly available brain transcriptome data of individuals with ASD and Tourette syndrome (Chapter 2). My second aim was to investigate the NDD proteome in immune cells: I performed a proteomic investigation of peripheral blood cells from two cohorts of children with PANS compared to controls (Chapter 3). Finally, my goal was to further investigate the immune profile of these children, and NDDs as a whole. I established a functional TLR assay to assess immune responses of peripheral blood cells from children with PANS compared to cells from neurotypical control children (Chapter 4).

The work presented within this thesis overall highlights a dysregulated immune response in individuals with NDDs. Further research developing strategies presented within this body of work will streamline targeting identified dysregulated pathways in a more personalised approach to help individuals with NDDs.