Dup15q model mice exhibit impaired gastrointestinal motility and a constipation-like phenotype, alleviated by prucalopride.

Chromosome 15q duplication syndrome (Dup15q) is a neurodevelopmental disorder linked to autism spectrum disorder (ASD), involving increased copies of the 15q11.2-q13 region. About 80% of individuals with Dup15q experience gastrointestinal (GI) dysfunction, including constipation. The duplicated region encodes GABA receptor A subunits, affecting GABAergic signalling, while reduced serotonin (5-HT) levels impair neuronal activity and social behaviour in a mouse model of Dup15q (15q dup). Given that both GABA and serotonin are expressed in the enteric nervous system (ENS), this study investigates gastrointestinal dysfunction in a Dup15q mouse model and the potential role of Prucalopride (pre-existing 5-HT4 receptor agonist). Colon RNA extracts were analysed for GABA receptor subunit and serotonin-associated gene expression using quantitative PCR. Total GI transit was assessed by Carmine red dye gavage. Ex vivo colonic motility was analysed via video imaging. The GABA receptor A antagonist Bicuculline was used to assess GABAergic signalling. Prucalopride, a 5-HT4 receptor (5HT4R) agonist, was administered for six days, and its effects on GI transit and social interaction were evaluated. 15q dup mice exhibited elevated GABA receptor gene expression and reduced Tph2 and Htr4 expression in the colon. Total GI transit was delayed, and ex vivo colonic motility was slower and less extensive. Bicuculline further impaired colonic contractions, indicating enhanced GABAergic sensitivity. Prucalopride restored GI transit delays and improved social interaction, as evidenced by increased contact duration in social tests. 15q dup mice exhibit constipation-like gastrointestinal dysfunction, and prucalopride alleviated their delayed transit and improved social behaviour. These findings highlight a potential avenue for symptom-focused intervention in this model.