PERIPHERAL NEUROIMMUNE MECHANISMS UNDERLYING MECHANICAL ITCH HYPERSENSITIVITY ASSOCIATED WITH AUTISM SPECTRUM DISORDERS

Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting ~1% of the population and characterized by social communication deficits, repetitive behaviors, and prominent sensory abnormalities. In addition to altered tactile processing, many individuals with ASD develop cutaneous symptoms such as dry skin, eczema, and chronic itch, which severely impair quality of life. However, the mechanisms linking tactile hypersensitivity, itch, and ASD remain poorly understood. Here, we investigated the neurobiological and neuro-immune bases of mechanical itch hypersensitivity using the Shank3^ΔC/ΔC mouse model, which carries a human-relevant mutation associated with Phelan-McDermid syndrome. Behavioral assays revealed exaggerated scratching responses to normally non-pruritic mechanical stimuli, indicating mechanical alloknesis. Skin innervation analyses showed increased density of sensory fibers, with a marked contribution of TH-positive C-LTMRs (low-threshold C mechanoreceptors), accompanied by aberrant epidermal localization. Ex vivo skin–nerve recordings demonstrated altered C-LTMR electrophysiological properties, including elevated mechanical thresholds and abnormal firing patterns, while myelinated fibers were unaffected. Chemogenetic activation of peripheral TH-positive neurons reduced excessive scratching. In addition, Shank3^ΔC/ΔC mice exhibited skin alterations associated with elevated mast cell degranulation, consistent with a basal inflammatory state. Preliminary single-cell RNA sequencing of naïve skin further supports upregulation of pro-inflammatory genes across non-immune cell populations. Accordingly, pharmacological blockade of the pro inflammatory receptor IL-1R (interleukin-1) significantly attenuated mechanical itch hypersensitivity. Together, these findings reveal mechanical itch hypersensitivity in ASD driven by combined alterations in C-LTMR dysfunction and cutaneous inflammatory signaling, highlighting disrupted neuro-immune communication as a potential therapeutic target.