## 5 Discussion  
This work describes a mathematical model that qualitatively captures results reported by [PERSON] et al. (2013), where the authors showed that, at least in Ala56 mice, who overexpression SERT receptors and who exhibit behaviors that broadly align with core diagnostic features of ASD, hypoplastic ENS as a result of increased activity of SERT in the gut is predictive of ASD phenotype. The authors also show that pharmacological interventions that compensate for overexpression of SERT can restore ENS size even in Ala56 mice, and these animals have improvements in behavioral patterns, suggesting that ENS hypoplasia may have a causal link for at least a subset of ASD phenotypes.  
Scaling the model from mouse to human suggested that alterations in SERT expression alone may be insufficient to result in ENS hypoplasia and instead there exist three key mechanisms that affect this process: rate of serotonin synthesis, rate of serotonin clearance from the gut (such as through SERT receptors), and rate of serotonin-mediated ENS growth. Assuming inter-individual variability with respect to these parameters, conducting a simulation that varies all three of these factors revealed that one can generate a \"spectrum\" of projected ENS size, which can perhaps be correlated to ASD severity, an intriguing hypothesis that requires empirical verification.  
Interestingly, in the recent work by [PERSON] et al. (2018), the authors analyzed genetic factors that may account for ASD in multiplex families, i.e., families, where more than one child has ASD. The authors analyzed whole genome sequences of over four thousand people, including both autistic and non-autistic children, calculating a weighted sum of common variants linked to ASD, or the \"polygenetic risk score\". The authors showed that children with ASD with rare inherited variants of genes that are linked to autism had higher scores than would have been expected if they inherited the variant from a non-autistic parent. The authors suggested that autism inheritance follows a \"threshold model\", where a combination of rare and common variants increase the chances of an ASD diagnosis. Within the framework of this analysis, one can hypothesize that the three key classes of mechanisms identified by the model may reflect a subset of such combinations of rare and common genetic factors, and specifically variations in serotonin production, clearance, and impact on the ENS, and it is their confluence that could result in ASD phenotypes that are mechanistically linked to ENS hypoplasia. Interestingly, studies have shown an elevated incidence of ASD in children of mothers who took SSRIs during pregnancy, which seems to contradict results reported by (2013), who report that in Ala56 mice, the administration of SSRIs during pregnancy compensated for excessive activity of SERT and thus mitigated the effects of overexpressed SERT on the ENS. It is possible that this effect is a confounder: if the mother has serotonin-mediated depressive symptoms, she may already pass along the genetic variant that may pre-dispose the fetus to ASD; it is also possible that, in addition, there may be an environment where fetal exposure to serotonin during development is decreased (such as has been observed for prenatal exposure to nutrient limitations, for example [19]), potentially contributing to ENS hypoplasia. If that is the case, then it is the association between parental depression, which may be genetic on both sides, necessitating SSRI administration even during pregnancy, and not the SSRIs themselves, that may be revealed by these observations. While some studies suggest that the odds of an ASD diagnosis are indeed higher among children whose mothers had a lifetime history of bipolar disorder or depression [20], this hypothesis remains to be evaluated more thoroughly to determine the impact of relevant confounders.