Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability (1)
Autoantibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been linked to a number of clinical syndromes. CASPR2 is a neuronal adhesion molecule of the neurexin superfamily that is known to form a protein complex with shaker- type voltage-gated potassium channels (such as Kv1.1 and Kv1.2). Mice lacking CASPR2 have been shown to develop autistic traits at a behavioral level, associated with deficits in the migration of cortical inhibitory interneurons.
The CASPR2-IgG-treated mice had very high CASPR2 titers (maximal binding at 1:100, titrating out to 1:12,500 or higher). Mice treated with purified IgG from patient 1 developed a significant delayed-onset mechanical hypersensitivity when compared to control IgG-treated mice, beginning after 11 days of injections. Mice treated with purified IgG from patient 2 also developed a delayed-onset mechanical hypersensitivity, which was significantly different from the control IgG group 15 days after the initial injection.
CASPR2 is more easily accessible on the neuronal soma and clear binding of human IgG can be seen on the surface of sensory neurons. The ability of CASPR2 to increase pain-related behavior in mice could be due to its action in the peripheral nervous system, particularly at the level of the DRG. CASPR2-Ab may regulate sensory function by reducing CASPR2 protein levels leading to increased excitability in peripheral sensory neurons.
Cntnap2/ mice were hypersensitive to von Frey hair application, demonstrating a significantly lower withdrawal threshold compared to wild-type (WT) littermates. Cntnap2/ mice were also hypersensitive to noxious pinprick application, which causes a rapid reflex withdrawal response mediated by Ad fibers. When the hotplate was set at 53C there was a significant difference between groups, with Cntnap2/ mice having a shorter latency to response.
Medium-sized DRG neurons were significantly hyper-responsive to mechanical stimulation, both brush and noxious pinch, applied to the hindpaw when compared to controls. Small-sized DRG neurons from Cntnap2/ were also more responsive to pinch application, as well as noxious heat.
Both small- (diameter <25 mm) and medium-sized DRG neurons (diameter 25–35 mm) from Cntnap2/ mice had significantly lower rheo- bases than controls. IKD was significantly reduced in medium diameter Cntnap2/ neurons compared control. Kv1.2 expression was significantly reduced to 11.3% ± 2.5% of DRG neurons in Cntnap2/ mice.
Compared to Cntnap2+/+mice, D-hairs from Cntnap2/ mice showed mark- edly impaired adaption and continued to fire during the static phase of the stimulus at velocities of 75 mm/s.
Electrical stimulation of the receptive field revealed reduced thresholds in Cntnap2/ mice for the activation of A- and C-fibers. The cumulative total of neuronal events evoked by both A- and C-fibers was increased in Cntnap2/ mice compared to Cntnap2+/+.
DRG neurons treated with plasma from both patient 1 and 2 also had a significant reduction in rheobase compared to control. Furthermore, DRG neurons treated with patient 1 plasma displayed significantly increased repetitive firing in response to supra-threshold stimuli compared to control cells, although this effect was not seen in cells treated with plasma from patient 2.
Autoantibodies from patients with rheumatoid arthritis and complex regional pain syndrome can cause abnormal pain behavior in mice through modulation of the inflammatory response and altered production of immune mediators.