Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter

Abstract

Alterations in the serotonergic control of brain pathways responsible for facial-emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched fMRI brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. Here, we used REACT to estimate the dominant fMRI signal related to the serotonin transporter (5-HTT) distribution during processing of aversive facial expressions of emotion processing in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, i.e. a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of 5-HTT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptor maps. We found a baseline group difference in the 5-HTT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram shifted the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Our findings suggest that the 5HTT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.