Analysis of gastorintestinal problems in autism mouse models

2021 Fiscal Year Annual Research Report

• Project/Area Number: 20F20704
• Research Institution: Kobe University
• Host Researcher: 内匠 透 神戸大学, 医学研究科, 教授 (00222092)
• Foreign Research Fellow: BALASURIYA BALASURIYA 神戸大学, 医学研究科, 外国人特別研究員
• Project Period (FY): 2020-11-13 – 2023-03-31
• Keywords: autism

Outline of Annual Research Achievements

Autism is a highly prevalent neurological disorder characterized by impaired social interactions and stereotyped or repetitive behaviours. Autism-associated GI symptoms frequently present from early childhood to adulthood and patients with autism are approximately four-fold more likely to be hospitalized with GI disorders. GI function is regulated by the intrinsic enteric nervous system (ENS), a complex network of neurons extending along the length of the GI tract arranged in two plexuses, the submucosal and myenteric plexuses that predominantly regulate gut secretion and motility, respectively. We will characterize the GI phenotype in two preclinical models of autism (CHD8 and 15q mice) to identify therapeutic targets to treat GI dysfunction.
Chromosome 15q duplication Syndrome is a neurodevelopmental disorder. Approximately 80% of individuals with 15q duplications (15q dup) have gastrointestinal (GI) dysfunction, with frequent symptoms including gastroesophageal reflux and constipation. The duplicated region consists of genes encoding for GABA receptor A subunits and GABA is an important neurotransmitter in the Enteric Nervous System (ENS)t. 15q duplication causes reduced concentration of serotonin in the brain. The gut produces over 90% of the body's serotonin, and serotonin plays a vital role in the enteric neuronal circuitry that regulates gut motility. Therefore, we investigated GI dysfunction and the GABA and serotonin mediated neurotransmission in this Enteric nervous system of this model.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

The study of GI dysfunction in 15q dup mice is still ongoing. The quantification of enteric neuronal changes, including changes in neural firing capacities, measuring concentrations of GABA and serotonin in gut tissue, measuring the dry weight of faeces, thickness of the colonic mucus layer, and assessing behavioural changes with prucalopride treatment, is still ongoing.
We wanted to investigate the GI dysfunction in a preclinical CHD8 mutant mouse model of autism. Preliminary findings show that adult mice have a delayed GI transit. However, given that the GI disorders are more prevalent at earlier ages, research is now underway to study total GI transit and colonic motility in mice aged 4-5 weeks. To properly characterise the GI dysfunction in individuals, we will also investigate at enteric neuronal alterations and changes in enteric neural firing capabilities.
We are currently establishing the Multi electrode Array (MEA) setting to quantify the firing frequencies of Enteric neurons. This will aid in identifying electrophysiological changes between wild type and mutant enteric neurons.

Strategy for Future Research Activity

From May to November 2022 (until the conclusion of the JSPS fellowship), research on both the projects understanding GI dysfunction in 15q duplication preclinical mouse model and understanding GI dysfunction in CHD8 mutant mouse model will be carried out. We want to publish these ground-breaking discoveries in high-impact publications.
So far, MEA system has not been employed to investigate the firing properties of enteric neurones. We are the first to try this in enteric neurons, which will be widely used in the future. This unique strategy for studying the electrophysiology of enteric neurones will be published as a method paper in a journal such as Bio protocols.