Oxytocin receptor gene expression in the basal forebrain in autism: association with receptor binding levels and single nucleotide polymorphisms

Background: The brain’s oxytocin system has been implicated in the neurobiology of autism (ASD), given the role of oxytocin in modulating social function in humans and animals more broadly. Previous work from members of our group reported dysregulation in oxytocin receptor (OXTR) binding in postmortem tissue from the basal forebrain in donors with autism compared to unaffected control donors. This study follows up on those findings by investigating the potential genetic and gene expression changes that could be driving those differences. Methods: We used adjacent sections from the same specimens from our previous study and performed duplex fluorescent in situ hybridization to visualize and quantify OXTR mRNA in the ventral pallidum (VP) and in the cholinergic magnocellular neurons of the nucleus basalis of Meynert (NBM), visualized with choline acetyltransferase (ChAT). We genotyped the brain samples using a SNP microarray on extracted DNA. We then used regression models to test associations between OXTR binding density, OXTR mRNA levels, and relevant OXTR SNPs. Additionally, we tested for correlation between age and OXTR mRNA. Results: ASD specimens showed significantly greater OXTR mRNA than unaffected donors in both the VP and the NBM. Furthermore, this is the first demonstration of OXTRexpression in the cholinergic neurons of the human basal forebrain; 73% of OXTR signal in the images of the ChAT+ neurons were colocalized with the cholinergic neurons. OXTR binding levels from our previous study were positively associated with OXTR mRNA in the NBM of control specimens but not in ASD specimens, implying potential dysregulation at the level of protein translation or mRNA trafficking in the NBM in ASD. OXTR binding levels were not associated with OXTRmRNA in the VP of either group. We genotyped all specimens for three common SNPs in the OXTR gene that have been associated with ASD in the literature, but none significantly predicted levels of OXTR binding or gene expression in the NBM or VP. Conclusions: Taken together, our results contribute to a more nuanced picture triangulating variation in OXTR gene sequence, gene expression, protein levels, and human behavior. Trial Registration:Clinical trial number: not applicable.