Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Dawes, J. M. et al. (2018) Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron, 97(4), 806-822.e10. (doi: 10.1016/j.neuron.2018.01.033) (PMID:29429934)

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Abstract

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.

Item Type:Articles
Keywords:CASPR2, CNTNAP2, DRG, Kv1, autism, autoantibody, mechanosensation, pain, sensory neuron, voltage-gated potassium channel.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Iwagaki, Mr Noboru and Weir, Dr Gregory and Gutierrez-Mecinas, Dr Maria and Todd, Professor Andrew
Authors: Dawes, J. M., Weir, G. A., Middleton, S. J., Patel, R., Chisholm, K. I., Pettingill, P., Peck, L. J., Sheridan, J., Shakir, A., Jacobson, L., Gutierrez-Mecinas, M., Galino, J., Walcher, J., Kühnemund, J., Kuehn, H., Sanna, M. D., Lang, B., Clark, A. J., Themistocleous, A. C., Iwagaki, N., West, S. J., Werynska, K., Carroll, L., Trendafilova, T., Menassa, D. A., Giannoccaro, M. P., Coutinho, E., Cervellini, I., Tewari, D., Buckley, C., Leite, M. I., Wildner, H., Zeilhofer, H. U., Peles, E., Todd, A. J., McMahon, S. B., Dickenson, A. H., Lewin, G. R., Vincent, A., and Bennett, D. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Neuron
Publisher:Elsevier
ISSN:0896-6273
ISSN (Online):1097-4199
Published Online:08 February 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Neuron 97(4):806-822.e10
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
644161Defining pain circuitry in health and diseaseAndrew ToddWellcome Trust (WELLCOTR)102645/Z/13/ZINP - CENTRE FOR NEUROSCIENCE