Serotonin Signaling in the Enteric Nervous System and Connection to Autism Spectrum Disorder: A Translational Mathematical Model

Abstract

While the causes of autism spectrum disorder (ASD) remain unclear, some studies have shown that serotonin-mediated effects on the enteric nervous system (ENS) correlate with an ASD-like behavioral phenotype in mice. Introduced here is a mathematical model of interactions between gut serotonin and its impact on the ENS. The model was used to identify three key factors that affect ENS size, namely, serotonin production, its clearance, and its ability to act as a growth factor for the ENS. The model was used to reproduce experimentally reported results from a mouse model by Margolis et al. (2016), which connected serotonin-mediated ENS hypoplasia to an ASD phenotype. The proposed mathematical model was used to scale the quantified relationship from mice to humans to show how the combination of these three factors can translate to a quantifiable metric that could potentially be correlated to the ASD spectrum. A detailed discussion of how ENS hypoplasia could mechanistically affect CNS activity concludes this paper.