Brain, Gut and Immune Interactions in Autism Spectrum Disorder

Citation

Hsiao, Elaine Yih-Nien (2013) Brain, Gut and Immune Interactions in Autism Spectrum Disorder. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/DEVQ-1P16. https://resolver.caltech.edu/CaltechTHESIS:12172012-110932095

Abstract

Autism spectrum disorder (ASD) is a class of complex neurodevelopmental disabilities that are characterized by the presence and severity of stereotyped behaviors, impaired communication, and abnormal social interactions. The incidence of autism has rapidly increased to 1 in 88 children in the United States, making ASD one of the most significant medical and social burdens of our time. However, drugs are often used to treat autism-related conditions, including anxiety, hyperactivity, epilepsy, and obsessive-compulsive behaviors, and therapies for treating the core symptoms of autism are limited. Moreover, molecular diagnostics are not available for the reproducible identification of ASD; as yet, the disorder is diagnosed based on standardized behavioral assessments. Much research into ASD has focused on genetic, behavioral, and neurological aspects of the illness. However, primary roles for environmental risk factors and peripheral disruptions, such as immune dysregulation and gastrointestinal distress, have gained significant attention.

The work described in this thesis uncovers molecular mechanisms involved in the pathogenesis of autism-related endophenotypes in a mouse model of a primary autism risk factor, maternal immune activation (MIA). MIA is founded upon the strong epidemiological link between maternal infection and increased autism risk in the offspring. This risk factor can be translated to a mouse model with face and construct validity for autism, wherein pregnant mice injected with the immunogenic, double-stranded RNA poly(I:C) yield offspring with the core behavioral and neuropathological features of autism. Specifically, we report that MIA critically alters placental immune status and endocrine function, reflecting a key pathway by which fetal development may be disrupted to manifest in ASD-related phenotypes. We identify signature changes to the fetal brain transcriptome in response to multiple modes of MIA, highlighting a converging pathway involved in the development of autism-related behaviors and neuropathologies. We characterize peripheral, neural, and enteric immune alterations in MIA offspring and uncover an immune contribution to autism-related behavioral abnormalities. Finally we demonstrate that a microbe-based therapeutic can ameliorate intestinal pathology, metabolic function, and autism-related behaviors in MIA mice, which supports a role for the gut-immune-brain axis in ASD.

Thesis Files