Current approaches to treating ASD are limited and may only treat a small set of symptoms. Furthermore, ASD often presents with gastrointestinal (GI) disturbances by mechanisms yet to be fully understood. Multiple hyperactive coding variants of the serotonin (5-HT) transporter (SERT) have been identified in ASD, highlighting the potential for targeting SERT for treating ASD. However, the effect that SERT activity has on GI function has yet to be evaluated. Therefore, scientists, led by Professor Michael D. Gershon, at the Columbia University Irving Medical Center developed an innovative method that uses 5-HT4 receptor agonism as a treatment for both the behavioural and gastrointestinal abnormalities associated with Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is an increasingly common behavioural condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Scientists created a therapy that uses 5-HT4 receptor agonists as a treatment for both the behavioural and GI abnormalities associated with ASD.

Agonism of the 5-HT4 receptor has been found to lead to increased enteric nervous system neurogenesis and is efficacious in increasing GI motility. Therefore, by administering a 5-HT agonist, such as prucalopride, development defects associated with a mutation in SERT that would otherwise have reduced efficacy of enteric neuronal 5-HT as a growth factor can be alleviated. As a result, this technology provides a potential therapeutic capable of not only reversing the symptoms of ASD and GI dysfunction but also preventing them.

The method has been validated in a mouse model of ASD. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. Researchers propose that deficient 5-HT signaling during development may contribute to GI and behavioural features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. Therefore, this innovative method can be applied to individuals with ASD, obsessive-compulsive disorder and gastrointestinal mobility disorder.