Trigeminal ganglion neuron subtype‐specific alterations of Ca_V2.1 calcium current and excitability in a Cacna1a mouse model of migraine

Abstract

Non-technical summary Activation of trigeminal neurons innervating the meninges and release of proinflammatory peptides (in particular calcitonin gene-related peptide (CGRP)) from their terminals are believed to play a key role in generating migraine pain. A monogenic subtype of migraine (familial hemiplegic migraine type-1 (FHM1)) is caused by gain-of-function mutations in a neuronal voltage-gated calcium channel (Ca v 2.1) involved in controlling neurotransmitter release from many synaptic terminals including those of trigeminal neurons at the meninges. Using a FHM1 transgenic mouse model, we show that the migraine mutation produces gain-of-function (i.e. it increases calcium influx) in a subpopulation of trigeminal neurons that do not innervate the meninges. In contrast, the calcium channels of trigeminal neurons innervating the meninges and releasing CGRP are not affected by the mutation. Congruently, the migraine mutation does not alter CGRP release at the meninges. Our findings suggest that the facilitation of CGRP actions at the meninges does not contribute to the generation of headache in FHM1.Abstract Familial hemiplegic migraine type-1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in Ca V 2.1 (P/Q-type) calcium channels. The consequences of FHM1 mutations on the trigeminovascular pathway that generates migraine headache remain largely unexplored. Here we studied the calcium currents and excitability properties of two subpopulations of small-diameter trigeminal ganglion (TG) neurons from adult wild-type (WT) and R192Q FHM1 knockin (KI) mice: capsaicin-sensitive neurons without T-type calcium currents (CS) and capsaicin-insensitive neurons characterized by the expression of T-type calcium currents (CI-T). Small TG neurons retrogradely labelled from the dura are mostly CS neurons, while CI-T neurons were not present in the labelled population. CS and CI-T neurons express Ca V 2.1 channels with different activation properties, and the Ca V 2.1 channels are differently affected by the FHM1 mutation in the two TG neuron subtypes. In CI-T neurons from FHM1 KI mice there was a larger P/Q-type current density following mild depolarizations, a larger action potential (AP)-evoked calcium current and a longer AP duration when compared to CI-T neurons from WT mice. In striking contrast, the P/Q-type current density, voltage dependence and kinetics were not altered by the FHM1 mutation in CS neurons. The excitability properties of mutant CS neurons were also unaltered. Congruently, the FHM1 mutation did not alter depolarization-evoked CGRP release from the dura mater, while CGRP release from the trigeminal ganglion was larger in KI compared to WT mice. Our findings suggest that the facilitation of peripheral mechanisms of CGRP action, such as dural vasodilatation and nociceptor sensitization at the meninges, does not contribute to the generation of headache in FHM1.

Impact of A118G Polymorphism on the Mu Opioid Receptor Function in Pain

“…This study found that Ca V currents from trigeminal ganglion neurons are inhibited at lower morphine doses when the neurons are injected with human MOR-D mRNA as compared with the inhibition observed in neurons injected with MOR-N mRNA [11]. The discrepancy between this report and the previously mentioned studies could be due to the fact that trigeminal ganglia have several Ca V types contributing to the voltage gated calcium currents [28,29] while Lopez Soto et al [8] analyzed Ca V 2.2 transfected in HEK293 cells and Margas et al [7] studied SGC neurons where the Ca V 2.2 are the predominant voltage gated channels.…”

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

“…Many triggers of migraine in human also activate TG meningeal nociceptors in rodents (Levy and Strassman 2004;Strassman et al 1996;Zhang et al 2010). Furthermore, mutations of the P/Q-type voltage-gated Ca 2ϩ channel associated with familial hemiplegic migraine type-1 cause hyperexcitation of TG neurons, suggesting that migraine headache may result from abnormal membrane conductance changes of the primary af- ferent neurons in TG (Fioretti et al 2011;Hullugundi et al 2014;Tao et al 2012). We reason that the effects of TRESK mutations/variants on TG excitability would be a better predictor of their contributions to migraine susceptibility, relative to their effects on TRESK currents in heterologous expression systems.…”

“…This calls into question a direct causal relationship between TRESK dysfunction and migraine phenotype (Andres-Enguix et al 2012;Eising et al 2013;Lafreniere et al 2010). On the other hand, previous works have illustrated the importance of studying migraine-associated gene mutations in neurons involved in migraine pathophysiology (Fioretti et al 2011;Hullugundi et al 2014;Liu et al 2013;Tao et al 2012;Tottene et al 2009;van Den Maagdenberg et al 2004). While the Xenopus oocyte system is a powerful tool for ion channel research, it may have limitations in predicting the genotype-phenotype correlation between TRESK mutations/variants and migraine susceptibility.…”

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

“…The CACNA1A KI mice bear a gain-of-function mutation of the α subunit of the Ca v 2.1 neuronal calcium channel, which is typically detected in families suffering from familial hemiplegic migraine type 1 (FHM1), a severe and genetic form of migraine accompanied by hemiparesis [23]. KI mice show a higher sensitivity to the generation of Cortical Spreading Depression (CSD, the prodromic sign of migraine pain) and also a higher rate of release of pro-algogenic substances (such as CGRP) within the TG [24,25]. Taken together, the biochemical changes observed in purinergic transmission both at the central and the peripheral levels in KI mice could account for the higher susceptibility to migraine triggers in these animals (and, possibly, FHM1 patients) (see also below, Section…”