The Role of Schwann Cells in the Onset of Neuropathic Pain in Neurofibromatosis-1

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to benign tumors in the peripheral nervous system (PNS). Pain is a primary cause of decreased quality of life in NF1 patients. Specific loss of Nf1 in SCs and SC precursors is responsible for neurofibroma formation, but the role of SCs in nociception and pain development in NF1 is not known. Here, we wanted to determine whether Schwann cells (SCs), sensory neurons, or both contributed to neuropathic pain-like behaviors in an animal model of NF1. We performed behavioral assessments of mechanical sensitivity, and single unit electrophysiological recordings of sensory neurons using our ex vivo preparation from mice with SC specific (DhhCre;Nf1f/f) or sensory neuron specific (PirtCre;Nf1+/f) deletion of Nf1 and compared results to Nf1+/- mice and littermate controls. We then performed similar assessments in animals' wildtype for Nf1 with chemogenetic manipulation of SC calcium activity. Data was correlated with DRG gene expression using realtime PCR and nerve structure using electron microscopy. Findings show that Nf1 deletion in SCs produced mechanical hypersensitivity, while Nf1 deletion in sensory neurons did not. Behavioral hypersensitivity in the SC specific Nf1 mutants, correlated with sensitization of myelinated A-fiber nociceptors and unmyelinated polymodal C-fibers (CPM) to mechanical stimuli. This occurred with Remak bundle disruption but not tumor formation. Chemo-genetic manipulation of SC calcium activity induced mechanical hypersensitivity at the behavioral level and produced sensitization of CPM neurons to mechanical stimuli compared to CNO treated controls. The observed peripheral sensitization correlated with elevation of cytokines and growth factors in the L2/L3 DRGs. This suggests that alterations in SCs are directly responsible for changes in specific sensory neuron subtypes that possibly modulate neuropathic pain development in NF1. This study may help to identify novel cell-specific treatment strategies to ameliorate pain in NF1 patients.