Synaptic A-to-I RNA Editing in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is likely caused by a combination of genetic and environmental factors acting at a sensitive period of neuronal development. Studies show that in many cases ASD is a disorder of abnormal synaptic function. To better understand the interactions between genes and the environment that modulate synaptic function, this research investigated the role of adenosine-to-inosine (A-to-I) RNA editing in ASD. A-to-I RNA editing is a regulatory mechanism that takes place mostly in the brain, in which the sequence of RNA molecules, especially those making synaptic proteins, changes in response to environmental stimuli. Because tweaking the levels of A-to-I editing in model organisms (such as mice and flies) alters their behavior, it is thought that A-to-I RNA editing is one of the molecular mechanisms connecting environmental stimuli and behavioral outputs. Several lines of evidence suggest that A-to-I editing could be important in ASD, including findings of differential editing of synaptic candidate genes between postmortem cerebella of individuals with ASD and neurotypical controls. Investigators hoped to validate and expand these findings by examining many more genes in more brain regions and more individuals. Using targeted capture and ultradeep sequencing of RNA and DNA, they compared the patterns of neurodevelopmentally-regulated editing between brain regions, individuals, and groups. The hope was that this research would provide a comprehensive view of the potential extent of A-to-I editing alterations in ASD, and their contribution to the synaptic abnormalities underlying the disorder.