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

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

doi:10.1016/j.neuron.2018.01.033

Cited by 139 publications

(160 citation statements)

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“…In cases 1 and 3, pain was an important feature that resulted in limitation of activity. This is in keeping with a recent report of pain hypersensitivity in animal models of immune and genetic disruption of CASPR2 …”

Section: Discussionsupporting

confidence: 92%

Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies

Surana

Kumar

Pitt

et al. 2019

Develop Med Child Neuro

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Acquired neuromyotonia is a form of peripheral nerve hyperexcitability. In adults, pathogenic antibodies that target the extracellular domains of leucine‐rich glioma‐inactivated protein 1 (LGI1) and contactin‐associated protein‐like 2 (CASPR2) have been reported. We describe three paediatric patients with acquired neuromyotonia and CASPR2 and LGI1 serum antibodies. They all presented with acute‐onset myokymia and pain in the lower limbs; one patient also had muscle weakness. Electromyography was suggestive of peripheral nerve hyperexcitability. Two patients improved without immunotherapy; one treated patient remained immunotherapy‐dependent. Although not fatal, acquired paediatric neuromyotonia can be disabling. It is amenable to symptomatic treatment or may undergo spontaneous recovery. More severe cases may require rational immunotherapy. What this paper adds The symptoms of neuromyotonia may resolve spontaneously or may require sodium channel blockers. Patients with debilitating symptoms who are refractory to symptomatic therapy may require immunotherapy.

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Section: Discussionsupporting

confidence: 92%

Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies

Surana

Kumar

Pitt

et al. 2019

Develop Med Child Neuro

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“…Either immune- or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of K v 1 channel expression at the soma membrane. These data suggest a key role for CASPR2 in regulating cell-intrinsic DRG neuron excitability (Dawes et al 2018). …”

Section: Dorsal Horn and Nociceptionmentioning

confidence: 90%

Substance P and pain chronicity

2018

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Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.

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“…This led to an increase in neurotransmitter release and a consecutive increase in postsynaptic excitatory responses (Scott et al., ). According to these findings, Kv1 surface expression was decreased at the soma of a subpopulation of DRG neurons in Cntnap2 KO mice, rendering them hyperexcitable (Dawes et al., ). These results strengthened the idea that CASPR2 affects intrinsic neuronal excitability by impacting Kv1 distribution at the neuronal membrane.…”

Section: Structure Expression and Function Of Caspr2mentioning

confidence: 99%

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Saint‐Martin

Joubert

Pellier‐Monnin

et al. 2018

Eur J of Neuroscience

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Contactin-associated protein-like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2-related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting-up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage-gated potassium channel (VGKC) complex that is composed of TAG-1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up-to-date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.

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

Cited by 139 publications

References 50 publications

Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies

Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies

Substance P and pain chronicity

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

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