Investigating the contribution of peripheral sensory neuron dysfunction to gastrointestinal-related phenotypes in mouse models of autism
- Awarded: 2020
- Award Type: Pilot
- Award #: 724817
Autism spectrum disorders (ASDs) are prevalent neurodevelopmental disorders, characterized by difficulties in social communication and interactions as well as restricted, repetitive behaviors. While ASDs are heterogeneous in etiology and severity, the vast majority of individuals with ASD also exhibit an array of co-morbid features, including atypical processing of sensory stimuli and gastrointestinal (GI) issues. Despite the prevalence and impact of GI issues in ASD, the causes of GI dysfunction in ASD are unknown. Further, the basic biology of the neural circuits encoding GI signals is not well understood. Peripheral sensory neurons of the dorsal root ganglia (DRG) that innervate the GI tract are critical for GI function, yet little is known about the development or function of these neurons.
Recent studies have focused on the contributions of the peripheral nervous system to ASD phenotypes, including sensory dysfunction. Previously, Lauren Orefice and colleagues found that a range of genetic mouse models of ASD exhibit over-reactivity to skin stimulation, and this over-reactivity is due to abnormal peripheral sensory neuron function. Light touch abnormalities resulting from ASD-associated gene deletion in peripheral sensory neurons of the DRG during development also lead to altered brain development and some ASD-related behaviors in mice1,2. This research identified that peripheral sensory neurons—neurons outside the brain—are key sites at which ASD-related gene mutations have a critical impact.
That some types of peripheral sensory neurons cause abnormal touch reactivity in mice may provide clues regarding GI abnormalities in ASD. In the current project, Orefice’s team will iteratively combine genetics, behavior, anatomy and electrophysiology in mice to investigate the development and function of DRG neurons that innervate the GI tract. The team will also determine whether this neuronal population is dysfunctional and contributes to GI-related phenotypes in mouse models of ASD, with a focus on the Mecp2 gene. This work aims to elucidate basic principles underlying GI physiology and provide insight regarding the mechanisms through which GI dysfunction occurs in ASD.