title: A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1.
abstract: Missense mutation R192Q in the CACNA1A gene causes familial hemiplegic migraine type-1 (FHM1), a monogenic subtype of migraine with aura. Using knock-in (KI) gene targeting we introduced this mutation into the mouse gene and generated a transgenic mouse model to investigate basic mechanisms of migraine pathophysiology. While FHM1 R192Q KI trigeminal ganglia were previously shown to exhibit constitutive up-regulation of ATP-gated P2X3 receptors, little is known about the firing properties of trigeminal sensory neurons, which convey nociceptive inputs to higher brain centers. We patch-clamped trigeminal sensory neurons to search for differences in firing properties between wildtype (WT) and KI cells in culture. Although various subclasses of trigeminal neurons were observed with respect to their firing patterns evoked by intracellular current injection, their distribution among WT and KI cells was similar with only small differences in rheobase or input resistance values. However, when neurons were excited by either α,β-methyl-ATP to stimulate P2X3 receptors or capsaicin to activate transient receptor potential vanilloid (TRPV1) receptors, the firing threshold in KI neurons was significantly lowered and followed by a larger number of spikes. Activation by α,β-methyl-ATP was associated with a transient cluster of action potentials, while capsaicin elicited more persistent firing. Using α,β-methyl-ATP or capsaicin, two functional classes of WT or KI neurons were distinguished according to the first spike latency, which suggests that a subgroup of neurons may be indirectly activated, probably via crosstalk between neurons and satellite glial cells. Thus, our results are consistent with reported facilitated trigeminal pain behavior of FHM1 R192Q KI mice.
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: swathihk@gmail.com.
authors.forename: S K
authors.initials: SK
authors.lastname: Hullugundi
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: alessioansuini@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Ansuini
authors.affiliation: Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands. Electronic address: m.d.ferrari@lumc.nl.
authors.forename: M D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands; Department of Human Genetics, Leiden Genetics University Medical Centre, 2300 RC Leiden, The Netherlands. Electronic address: maagdenberg@lumc.nl.
authors.forename: A M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: nistri@sissa.it.
authors.forename: A
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D051379:Mice; D008881:Migraine Disorders / Q000235:genetics / Q000503:physiopathology*; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011984:Sensory Receptor Cells / Q000502:physiology*; D012668:Trigeminal Ganglion / Q000503:physiopathology
chemical_list: D020864:Calcium Channels, N-Type
keywords: ATP; P2X3 receptors; TRPV1 receptors; capsaicin; purinergic