LAYER-SPECIFIC AXON INITIAL SEGMENT PLASTICITY UNDERLIES CORTICAL HYPEREXCITABILITY IN TRIGEMINAL PAIN

Neuropathic pain, major public health problem affecting 7 to 10 % of the population (Moisset et al., 2020), arises from peripheral lesion, causing maladaptive plasticity and central sensitization. Orofacial neuropathic pains, caused by diseases or traumas to the trigeminal nervous system, constitute a major therapeutic challenge to healthcare professionals (Moreau and Boucher, 2022) and the mechanism by which they emerge is still poorly understood. Several studies suggest that neuropathic pain may arise from primary somatosensory cortex (S1) hyperactivity (Thibault et al., 2016; Xiong et al., 2017). Using behavioral analysis, ex vivo electrophysiology, immunofluorescence and computational modeling, our study aimed to decipher the nature and the cellular origin of S1 hyperactivity in a murine model of orofacial neuropathic pain (infraorbital nerve ligation IONL), focusing on S1 layers II/III and V pyramidal neurons (L2/3PC, L5PC). Performing patch-clamp experiments in both female and male rats, we observed a layer-specific increase of L5PC intrinsic excitability in the barrel field cortex of neuropathic animals on the contralateral side of the nerve ligation. This hyperexcitability is associated with a 5-µm-increase axon initial segment (AIS) length in these neurons. The L2/3PC shows no change in excitability or morphology. Using a computational approach, we found that AIS length increase is sufficient to explain L5PC cellular hyperexcitablity, leading to hyperactivity at the network level. These results suggest that orofacial neuropathic pain is associated with exacerbated neuronal activity due to AIS plasticity at the S1 cortical level.