Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability

John M. Dawes, Greg A. Weir, Steven J. Middleton, Ryan Patel, Kim I. Chisholm, Philippa Pettingill, Liam J. Peck, Joseph Sheridan, Akila Shakir, Leslie Jacobson, Maria Gutierrez-Mecinas, Jorge Galino, Jan Walcher, Johannes Kühnemund, Hannah Kuehn, Maria D. Sanna, Bethan Lang, Alex J. Clark, Andreas C. Themistocleous, Noboru IwagakiSteven J. West, Karolina Werynska, Liam Carroll, Teodora Trendafilova, David A. Menassa, Maria Pia Giannoccaro, Ester Coutinho, Ilaria Cervellini, Damini Tewari, Camilla Buckley, M. Isabel Leite, Hendrik Wildner, Hanns Ulrich Zeilhofer, Elior Peles, Andrew J. Todd, Stephen B. McMahon, Anthony H. Dickenson, Gary R. Lewin, Angela Vincent, David L. Bennett*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Citations (Scopus)
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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. Dawes et al. show that CASPR2, the target of an autoimmune pain disorder, regulates sensory function through tuning of primary afferent excitability. Human autoantibodies to CASPR2 cause pain-related hypersensitivity and enhance DRG cell excitability through reduced Kv1 channel function.

Original languageEnglish
Article numbere10
Pages (from-to)806-822
JournalNeuron
Volume97
Issue number4
Early online date8 Feb 2018
DOIs
Publication statusPublished - 21 Feb 2018

Keywords

  • autism
  • autoantibody
  • CASPR2
  • CNTNAP2
  • DRG
  • Kv1
  • mechanosensation
  • pain
  • sensory neuron
  • voltage-gated potassium channel

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