Integrating Autism Spectrum Disorder Pathophysiology: Mitochondria, Vitamin A, CD38, Oxytocin, Serotonin and Melatonergic Alterations in the Placenta and Gut.

BACKGROUND: A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both. METHODS: Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article. RESULTS: Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia, as well as more general prenatal stressors, modulate the likelihood of offspring ASD. CONCLUSION: Such a mitochondria-focussed integrated model of the pathophysiology of ASD has important preventative and treatment implications.

Autism Spectrum Disorders: Role of Pre- and Post-Natal GammaDelta (γδ) T Cells and Immune Regulation.

BACKGROUND: It is widely accepted that alterations in immune functioning are an important aspect of the pathoetiology and pathophysiology of autism spectrum disorders (ASD). A relatively under-explored aspect of these alterations is the role of gammaDelta (γδ) T cells, prenatally and in the postnatal gut, which seem important hubs in driving the course of ASD. METHODS: The present article describes the role of γδ T cells in ASD, including their interactions with other immune cells shown to be altered in this spectrum of conditions, including natural killer cells and mast cells. RESULTS: Other risk factors in ASD, such as decreased vitamins A & D, as well as toxin-associated activation of the aryl hydrocarbon receptor, may also be intimately linked to γδ T cells, and alterations in the regulation of these cells. A growing body of data has highlighted an important role for alterations in mitochondria functioning in the regulation of immune cells, including natural killer cells and mast cells. This is an area that requires investigation in γδ T cells and their putative subtypes. CONCLUSION: It is also proposed that maternal stress may act through alterations in the maternal microbiome, leading to changes in how the balance of short-chain fatty acids, such as butyrate, which may act to regulate the placenta and foetal development. Following an overview of previous research on immune, especially γδ T cells, effects in ASD, the future research implications are discussed in detail.