Transcriptomic Profiling of the Amygdala of Children With Autism Spectrum Disorder

ABSTRACT A growing number of studies point to a key role of the amygdala in Autism Spectrum Disorders (ASD). The amygdala is involved in several processes in ASD including emotional valence, facial recognition, regulation of social learning, empathy, and anxiety. Brain imaging and postmortem studies demonstrate altered amygdala development in children with ASD, associated with impairment in social behavior and anxiety. There is limited information regarding the molecular pathology of the amygdala in children with ASD. We conducted RNAseq profiling on postmortem amygdala samples from male children (4–14 years old) with ASD ( n = 8) and normotypic male children ( n = 6). Furthermore, we conducted drug repurposing analysis to identify compounds predicted to reverse the transcriptomic signatures identified in order to identify potential therapeutic targets for development of early intervention treatments. Full transcriptome gene expression profiling implicated molecular pathways involved in neuroimmune signaling, glycogen and carbohydrate metabolism, matrix metalloproteases, neurodevelopment, estrogen receptor signaling, and synaptic signaling. Targeted pathway analysis of the top 10% of genes ranked by log 2 fold change implicated pathways involved in extracellular matrix organization (ECM), immune signaling, and synaptic signaling. Our drug repurposing analysis identified sleep modifying compounds and anti‐inflammatory compounds including COX2 and GSK3 inhibitors amongst the top predicted therapeutic compounds. PDGF receptor tyrosine kinase inhibitors were identified as a top potential therapeutic mechanism of action. Collectively, we identified alterations in immune signaling, ECM, and synaptic signaling in the amygdala of children with ASD. Furthermore, our findings highlight a number of potential therapeutic drug targets for development of early intervention strategies.