Disentangling Schwann Cell and Neuronal TRPA1 Function in Mouse Models of Familial Episodic Pain Syndrome

Summary Familial Episodic Pain Syndrome (FEPS) is a rare inherited disorder characterized by episodes of severe upper-body pain triggered by different stimuli including cold, stress, or fasting. A gain-of-function point mutation (N855S) in the Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel has been identified in affected individuals, altering its biophysical properties, and leading to sustained nociceptive signaling. While TRPA1 is predominantly studied in sensory neurons, recent findings highlight its key modulatory role for Schwann cells in chronic pain. Here, we investigated the cell-specific contributions of mutant TRPA1 (TRPA1*) in FEPS by developing mouse models with TRPA1* selectively expressed in either Schwann cells or sensory neurons, using CRISPR-based and Cre-loxP strategies. Patch-clamp analyses confirmed that TRPA1* exhibits enhanced current responses to agonists compared to wild-type. Through behavioral assays we revealed that TRPA1* expressed in sensory neurons mediates acute nociception, while TRPA1* in Schwann cells drives mechanical allodynia in response to subthreshold doses of TRPA1 agonists and to physiological pain triggers commonly observed in FEPS patients, including fasting, cold exposure, and restraint stress. Pain responses were associated with the increase in reactive oxygen species (ROS) and accumulation of 4-hydroxynonenal (4-HNE) in TRPA1* sciatic nerves and these effects were reduced by a treatment with an antioxidant. We reveal distinct roles of neuronal and non-neuronal TRPA1 in pain and provide novel in vivo models to investigate the mechanisms of chronic pain in FEPS and related channelopathies. Overall, this study offers new insights into the development of targeted therapies for Schwann cell-TRPA1 to relieve pain in affected individuals.