ATF3 PROMOTES INTRINSIC DRG NEURON HYPEREXCITABILITY AND NEUROMA PAIN AFTER TRANSECTION

Peripheral nerve injury robustly induces the transcription factor ATF3 in dorsal root ganglion (DRG) neurons, yet its contribution to chronic pain remains unresolved. Using Vglut2-lineage Atf3 conditional knockout mice, we tested ATF3 function in two neuropathic pain models with distinct injury states: sciatic nerve transection, which produces neuroma/ongoing pain, and spared nerve injury (SNI), which produces spared-fiber allodynia. ATF3 deletion attenuated transection-induced neuroma hypersensitivity and reduced spontaneous pain-like paw lifting. In contrast, ATF3 deletion did not alter tactile allodynia after SNI, quantified as 50% paw withdrawal threshold in the sural territory, suggesting a selective requirement for ATF3 in axotomy/neuroma contexts rather than spared-fiber hypersensitivity. To probe cell-intrinsic mechanisms, we examined excitability in naïve primary DRG cultures. ATF3-deficient neurons showed reduced spontaneous network activity on multi-electrode arrays, and whole-cell patch-clamp recordings were consistent with decreased intrinsic excitability, including increased rheobase and elevated action potential threshold. Together, these data support a model in which ATF3 promotes neuroma pain after transection, at least in part by enhancing intrinsic DRG neuron excitability, and nominate ATF3 effectors as therapeutic entry points for neuroma pain.