Dorsal root ganglion neuron dysfunction contributes to autism-related gastrointestinal deficits in mice

Abstract

Chronic gastrointestinal (GI) dysfunction, including pain, is highly prevalent in autism spectrum disorder (ASD). Although GI dysfunction severely impacts quality of life and correlates with exacerbated social difficulties and anxiety in autistic individuals, the neural mechanisms underlying GI abnormalities in ASD remain poorly understood. Here, using genetic, anatomical, physiological, and behavioral approaches across multiple ASD mouse models, we demonstrated that heightened visceral pain is a convergent phenotype across genetically distinct mouse models for ASD, including Mecp2, Cdkl5, or Shank3 loss-of-function mutants. We identified colon-innervating dorsal root ganglion (DRG) neurons as a key site of dysfunction, where loss of Mecp2 causes increased peripheral innervation and cell-autonomous hyperexcitability in these neurons. This colon-innervating DRG neuron dysfunction leads to enhanced spinal cord neuron responses to both innocuous and noxious colon stimulation, revealing a bottom-up amplification of visceral signals across the gut-DRG-central nervous system axis. Strikingly, selective disruption of Mecp2 restricted to colon-innervating DRG neurons is sufficient to drive both visceral hypersensitivity and anxiety-like behaviors, establishing a causal link between colon-innervating DRG neuron dysfunction and brain-driven behavioral phenotypes. Together, these findings identify colon-innervating DRG neurons as a previously unrecognized node of ASD pathology and reveal a peripheral sensory circuit mechanism through which GI dysfunction can shape central nervous system function and behavior.