While autism spectrum disorder (ASD) is highly heterogeneous in etiology and severity, the majority of autistic individuals exhibit an array of co-morbid symptoms, including aberrant reactivity to sensory stimuli and chronic difficulties with feeding behaviors. Surprisingly, the vast majority of feeding issues in ASD are not due to heightened sensitivity to tastes or a lack of appetite, but rather heightened sensitivity to food textures. Restricted diet due to oral texture hypersensitivity can result in a range of additional comorbid problems, including nutritional deficiencies, changes in body weight and gut microbiome disruptions. While oral texture hypersensitivity and concomitant feeding issues are a significant and persistent problem for many autistic individuals, the mechanisms underlying oral texture sensitivity disruptions in ASD are not understood.

The majority of ASD research has focused on brain-specific mechanisms and circuits, with less attention to the contributions of the peripheral nervous system to ASD symptoms. Previously, Lauren Orefice and colleagues found that a range of mouse models for ASD exhibit over-reactivity to skin stimulation, and this over-reactivity is due to dysfunction of peripheral sensory neurons of the dorsal root ganglia (DRG)^{1, 2}. Light touch abnormalities resulting from ASD-related gene deletion in DRG neurons during development also lead to altered brain development and some ASD-related behaviors in adult mice. Orefice and her team’s research therefore proposes a revision of the dominant view that ASD arises exclusively from abnormal brain function and that dysfunction in peripheral sensory neurons may also play a critical role in the development of the condition.

That some types of peripheral sensory neurons cause abnormal touch reactivity in mice may provide clues regarding oral texture abnormalities in ASD. In this project, Orefice and colleagues plan to study cellular and circuit-level mechanisms of dysfunction underlying oral texture hypersensitivity in ASD mouse models. They propose that similar to DRG peripheral sensory nerves that innervate the skin, peripheral somatosensory neurons of the trigeminal ganglia that innervate the oral cavity and transmit touch/texture information from the tongue are dysfunctional in ASD. Orefice’s team hypothesizes that loss of ASD risk genes causes trigeminal neuron dysfunction, resulting in hypersensitivity to tongue stimulation, altered encoding of oral texture information in the brain and, ultimately, altered feeding behaviors.

By iteratively combining genetics, behavior, anatomy and electrophysiology in mice, this proposal aims to: (1) assess whether mutations in ASD risk genes disrupt oral texture preferences, (2) determine if loss of ASD risk genes alters the functional properties of tongue-innervating trigeminal ganglia neurons and (3) understand how trigeminal ganglia neuron dysfunction may impact oral texture encoding in the brain. These initial studies will focus on mice harboring mutations in Gabrb3 or Shank3.

This project presents a potential paradigm shift in how we approach the study and treatment of ASD, will elucidate basic principles underlying oral texture encoding in the nervous system, and provide key insight regarding the mechanisms through which oral texture hypersensitivity and feeding behavior issues occur in ASD. Findings from these studies may change how we think about ASD pathophysiology and also highlight possible novel therapeutic targets for ASD treatments.

1. Orefice L.L. et al. Cell 166, 299–313 (2016) PubMed
2. Orefice L.L. et al. Cell 178, 867–886 (2019) PubMed