Sex-dependent differences in pain and sleep in a porcine model of Neurofibromatosis type 1

Khanna, R.; Moutal, A.; White, K.; Chefdeville, A.; Negrao de Assis, P.; Cai, S.; Swier, V. J.; Bellampalli, S. S.; Giunta, M. D.; Darbro, B. W.; Quelle, D. E.; Sieren, J. C.; Wallace, M. R.; Rogers, C. S.; Meyerholz, D. K.; Weimer, J. M.

doi:10.1101/495358

bioRxiv · 10.1101/495358

Sex-dependent differences in pain and sleep in a porcine model of Neurofibromatosis type 1

Khanna, R.·Moutal, A.·White, K.·Chefdeville, A.·Negrao de Assis, P.·Cai, S.·Swier, V. J.·Bellampalli, S. S.·Giunta, M. D.·Darbro, B. W.·Quelle, D. E.·Sieren, J. C.·Wallace, M. R.·Rogers, C. S.·Meyerholz, D. K.·Weimer, J. M.

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Abstract

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder resulting from germline mutations in the NF1 gene, which encodes neurofibromin. Patients experience a variety of symptoms, but pain in the context of NF1 remains largely underrecognized. Here, we characterize nociceptive signaling and pain behaviors in a miniswine harboring a disruptive NF1 mutation (exon 42 deletion). We explore these phenotypes in relationship to collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin. Mechanistically, we found two previously unknown phosphorylated residues of CRMP2 in NF1+/ex42del pig dorsal root ganglia (DRGs) and replicated increased voltage-gated calcium channel currents in NF1+/ex42del pig DRGs previously described in rodent models of NF1. We present the first characterization of pain-related behaviors in a pig model of NF1, identifying unchanged agitation scores, lower tactile thresholds (allodynia), and decreased response latencies to thermal laser stimulation (hyperalgesia) in the NF1 mutant animals; NF1+/ex42del pigs demonstrated sexually dimorphic behaviors. NF1+/ex42del pigs showed reduced sleep quality and increased resting, two health-related quality of life symptoms found to be comorbid in people with NF1 pain. Finally, we show decreased depolarization-evoked calcium influx in both wildtype and NF1+/ex42del pig DRGs treated with CRMP2 phosphorylation inhibitor (5)-lacosamide. Our data supports use of NF1+/ex42del pigs as an ideal model for studying NF1-associated pain and are a better model for understanding the pathophysiology of NF1 compared to rodents. Moreover, our findings demonstrate that interfering with CRMP2 phosphorylation might be a promising therapeutic strategy for NF1-related pain management.

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Khanna, R., Moutal, A., White, K., Chefdeville, A., Negrao de Assis, P., Cai, S., Swier, V. J., Bellampalli, S. S., Giunta, M. D., Darbro, B. W., Quelle, D. E., Sieren, J. C., Wallace, M. R., Rogers, C. S., Meyerholz, D. K., Weimer, J. M.. 2018-12-20. Sex-dependent differences in pain and sleep in a porcine model of Neurofibromatosis type 1. https://doi.org/10.1101/495358

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