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A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1.
Neuroscience 2014; 266:244-54N

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+Show Affiliations

Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: swathihk@gmail.com.Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: alessioansuini@gmail.com.Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands. Electronic address: m.d.ferrari@lumc.nl.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.Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: nistri@sissa.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24583041

Citation

Hullugundi, S K., et al. "A Hyperexcitability Phenotype in Mouse Trigeminal Sensory Neurons Expressing the R192Q Cacna1a Missense Mutation of Familial Hemiplegic Migraine Type-1." Neuroscience, vol. 266, 2014, pp. 244-54.
Hullugundi SK, Ansuini A, Ferrari MD, et al. A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1. Neuroscience. 2014;266:244-54.
Hullugundi, S. K., Ansuini, A., Ferrari, M. D., van den Maagdenberg, A. M., & Nistri, A. (2014). A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1. Neuroscience, 266, pp. 244-54. doi:10.1016/j.neuroscience.2014.02.020.
Hullugundi SK, et al. A Hyperexcitability Phenotype in Mouse Trigeminal Sensory Neurons Expressing the R192Q Cacna1a Missense Mutation of Familial Hemiplegic Migraine Type-1. Neuroscience. 2014 Apr 25;266:244-54. PubMed PMID: 24583041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1. AU - Hullugundi,S K, AU - Ansuini,A, AU - Ferrari,M D, AU - van den Maagdenberg,A M J M, AU - Nistri,A, Y1 - 2014/02/27/ PY - 2013/10/14/received PY - 2014/01/20/revised PY - 2014/02/07/accepted PY - 2014/3/4/entrez PY - 2014/3/4/pubmed PY - 2015/2/14/medline KW - ATP KW - P2X3 receptors KW - TRPV1 receptors KW - capsaicin KW - purinergic SP - 244 EP - 54 JF - Neuroscience JO - Neuroscience VL - 266 N2 - 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. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/24583041/A_hyperexcitability_phenotype_in_mouse_trigeminal_sensory_neurons_expressing_the_R192Q_Cacna1a_missense_mutation_of_familial_hemiplegic_migraine_type_1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(14)00124-9 DB - PRIME DP - Unbound Medicine ER -