Disorders in gut function, notably chronic constipation, are a major issue for autistic patients and their families, affecting up to 80% of patients. However, the mechanisms underlying these gut disorders are unknown. Many gene mutations identified in autism patients disrupt the proteins that regulate communication between nerve cells in the brain. It is our hypothesis that some of these mutations alter the behavior of the intrinsic nervous system of the gastrointestinal (GI) tract, the enteric nervous system (ENS), to produce gut problems. Surprisingly, there has been virtually no research addressing neural mechanisms underlying gut symptoms of autism (or autism spectrum disorders [ASDs] in general), and it is not clear whether these symptoms are due to the behavioral problems of ASD or are directly due to problems within the ENS. A major reason has been a lack animal models of ASD that allow studies of gut function in isolation from the central nervous system. Recently, several mouse models of autism have been validated behaviorally and this project takes advantage of two of them. This project focuses on colonic function in the NL3 mouse model of autism. These mice express a human gene mutation in a protein called neuroligin 3, which is known to be important for brain function and cell adhesion, identified in two brothers with ASD. We have recently shown that several adhesion molecules, including neuroligin 3, that are important for brain wiring and neuronal function are also present in the ENS. This indicates that they influence neural control of gut function. Through the measurement of regular, stereotyped contractions in isolated colonic tissue, we have shown altered colon function in these NL3 mice in response to drugs acting on a key chemical for communication between nerve cells in the brain, GABA. The function of GABA in the ENS is relatively under-studied, so its role is uncertain. The study will use a series of relatively simple assays to compare gut involvement in the NL3 mouse model of ASD with another model, the Balb/cJ mouse, with the long-term aim of identifying therapeutic targets for gastroenterological treatment specific to autism. Further, by identifying the roles of enteric GABA neurons and their targets in both normal and autistic mice, the project will help clarify mechanisms by which the neuroligin 3 mutation can modify neural circuits and so produce behavioral dysfunction. This study will provide the first evidence that a mutation associated with ASD in humans also produces gut dysfunctions. Thus, it will demonstrate that at least some gut problems experienced by ASD patients are not secondary to their behavior, but are a primary symptom of the disorder. This should have major consequences for treatment of gut problems in ASD patients by focusing the attention of relevant clinicians on peripheral, rather than central, dysfunctions.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
