Most autistic individuals report sensory over-reactivity and gastrointestinal problems, which dramatically affect their lives and their caregivers. Recently, we discovered that peripheral sensory neurons of the dorsal root ganglia (DRG) are a key locus of dysfunction for these ASD phenotypes. Multiple, disparate ASD-related gene mutations (MECP2, GABRB3 or SHANK3) in DRG neurons, but not in neurons of the brain, lead to tactile hypersensitivity in adult mice. Consistently, our preliminary data reveal that DRG neuron dysfunction in ASD models impairs neural processing of colon-directed stimuli and disrupts gastrointestinal function to cause increased gastrointestinal pain in adult mice. Strikingly, altered sensory experience during development due to selective disruption of ASD-associated genes in DRG neurons also leads to other ASD phenotypes, including changes in social behaviors in adult mice. Our results therefore propose the intriguing possibility that sensory over-reactivity is a primary contributor to social impairments in ASD. However, the mechanisms by which aberrant sensory processing disrupts social behaviors in ASD are unknown.

We hypothesize that DRG neuron dysfunction in ASD alters the development of primary somatosensory cortex (S1) and disrupts S1 representations of skin- and colon-directed stimuli. We predict that aberrant sensory representations impact the development of the connections between S1 and anterior cingulate cortex (ACC), which impairs transmission of sensory information to ACC during social interactions and causes atypical social decision-making in ASD. We will test these hypotheses by comparing mice with germline or selective loss of ASD-associated genes (Mecp2, Gabrb3 or Shank3) in peripheral sensory neurons and their control littermates across development to adulthood. First, we will measure how DRG neuron dysfunction disrupts S1 responses to skin- and colon-directed stimuli using in vivo electrophysiology. We will develop new optogenetics approaches to map the connectivity between cell types within S1 and measure how the connectivity changes with aberrant DRG neuron function. Second, we will use circuit tracing and in vivo electrophysiology to investigate how ASD-related gene mutations in DRG neurons change the connectivity and information flow from S1 to ACC. We will also use high-density electrophysiology in ACC during a novel social decision-making assay we developed to test for changes in the representations of social interactions due to DRG neuron dysfunction.

Together, our work aims to unite two major ASD phenotypes – sensory over-reactivity and social impairments – by demonstrating a mechanistic link from developmental sensory circuit abnormalities to changes in social behavior.