Trigeminal ganglion neuron subtype-specific alterations of Ca V2.1 calcium current and excitability in aCacna1amouse model of migraine

B. Fioretti, L. Catacuzzeno, L. Sforna, M. B. Gerke-Duncan, A. M J M van den Maagdenberg, F. Franciolini, M. Connor, D. Pietrobon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Familial hemiplegic migraine type-1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in Ca V2.1 (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 V2.1 channels with different activation properties, and the Ca V2.1 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.

Original languageEnglish
Pages (from-to)5879-5895
Number of pages17
JournalJournal of Physiology
Volume589
Issue number23
DOIs
Publication statusPublished - Dec 2011

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