Modulation of Autism-Associated Serotonin Transporters by Palmitoylation: Insights into the Molecular Pathogenesis and Targeted Therapies for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a developmental disorder of the nervous system characterized by a deficiency in interpersonal communication skills, a pathologic tendency for repetitive behaviors, and highly restrictive interests. The spectrum is a gradient-based construct used to categorize the widely varying degrees of ASD phenotypes, and has been linked to a genetic etiology in 25% of cases. Prior studies have revealed that 30% of ASD patients exhibit hyperserotonemia, or severely elevated whole blood serotonin (5HT), implicating the serotonergic system in the pathogenesis of ASD. Likewise, escitalopram, a selective-serotonin reuptake inhibitor (SSRI), has been demonstrated to effectively improve core ASD symptoms potentially by modulating abnormal brain activation in ASD patients. Molecular studies have uncovered proband patients with rare mutations in the serotonin transporter (SERT) that manifest enhanced surface expression and 5HT transport capacity, suggesting that abnormal enhancement of SERT function may be involved in the pathogenesis of ASD. Here, we reveal that palmitoylation is enhanced in the ASD SERT F465L and L550V coding variants, and confirm prior reports of enhanced kinetic activity and surface expression of F465L. Furthermore, treatment of F465L with the irreversible palmitoyl acyl-transferase inhibitor, 2-bromopalmitate (2BP), or escitalopram, rectified enhanced F465L palmitoylation, surface expression, and transport capacity to basal WT levels. Overall, our results implicate disordered SERT palmitoylation in the pathogenic mechanism of ASD, with basal recovery of these processes following escitalopram treatment providing insight into its molecular utility as an ASD therapeutic.