Caecal dysfunction in the NL3R451Cmouse model of autism

Abstract

AbstractThe mouse caecum is a pouch-like structure that is anatomically similar to the human appendix and is hypothesised to serve as a reservoir for commensal bacteria. The gastrointestinal tract is also home to the largest immunological organ of the body and the enteric nervous system (ENS), which regulates gut motility and secretion. The caecum is therefore an ideal location to study neuro-immune-microbe interactions in gut-brain communication. Individuals with Autism Spectrum Disorder (ASD; autism) frequently present with gastrointestinal symptoms in addition to core diagnostic behavioural features, implying a gut-brain link. More broadly, changes in gut-brain connectivity are now thought to play a critical role in a range of neurodevelopmental disorders. Here, we employed a mouse model of autism expressing a missense mutation in the neuroligin-3 post-synaptic protein that affects brain and enteric neuronal activity (NL3R451Cmice). We previously observed abnormal caecal ENS architecture and immune cell morphology in the caecal patch in this model, however it is unknown if caecal function is altered in NL3R451Cmice. Using a tri-cannulation approach to record motility patterns in the mouse caecum, we identified novel caecal motor complexes inex vivopreparations. Caecal permeability and neurally-evoked secretion levels were also studied. Key immune populations including gut macrophages and dendritic cells within the caecal patch were stained using immunofluorescence to investigate shifts in immune activity. Caecal motility patterns in NL3R451Cmice differed from wildtype littermates. Specifically, caecal motor complexes occurred at a higher frequency and for a shorter duration in NL3R451Cmice than in wildtype littermates. In NL3R451Cmice, neurally-evoked caecal secretion was reduced in response to the nicotinic acetylcholine receptor agonist (DMPP), but permeability was unchanged. Increased numbers of caecal patches were observed in NL3R451Cmice compared to wildtype, with no alterations in morphology of selected immune populations. Future research is warranted to better understand caecal function and how neuro-immune interactions in the caecum affect health and influence GI function in neurodevelopmental disorders via the gut-brain axis.