title: Differential trigeminovascular nociceptive responses in the thalamus in the familial hemiplegic migraine 1 knock-in mouse: a Fos protein study.
abstract: Familial hemiplegic migraine type 1 (FHM-1) is a monogenic subtype of migraine with aura caused by missense mutations in the CACNA1A gene, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels. Transgenic knock-in mice expressing the CACNA1A R192Q mutation that causes FHM-1 in patients show a greater susceptibility to cortical spreading depression, the likely underlying mechanism of typical human migraine aura. The aim of this study was to compare neuronal activation within the trigeminal pain pathways in response to nociceptive trigeminovascular stimulation in wild-type and R192Q knock-in mice. After sham surgery or electrical stimulation of the superior sagittal sinus for 2h, or stimulation preceded by treatment with naratriptan, mice underwent intracardiac perfusion, and the brain, including the brainstem, was removed. Fos expression was measured in the trigeminocervical complex (TCC) and the lateral (ventroposteromedial, ventrolateral), medial (parafascicular, centromedian) and posterior thalamic nuclei. In the TCC of wild-type animals, the number of Fos-positive cells increased significantly following dural stimulation compared to the sham control group (P<0.001) and decreased after naratriptan treatment (P<0.05). In R192Q knock-in mice, there was no significant difference between the stimulated and sham (P=0.10) or naratriptan pre-treated groups (P=0.15). The number of Fos-positive cells in the R192Q stimulated group was significantly lower compared to the wild-type stimulated mice (P<0.05). In the thalamus, R192Q mice tended to be more sensitive to stimulation compared to the sham control in the medial and posterior nuclei, and between the two strains of stimulated animals there was a significant difference in the centromedian (P<0.005), and posterior nuclei (P<0.05). The present study suggests that the FHM-1 mutation affects more rostral brain structures in this experimental paradigm, which offers a novel perspective on possible differential effects of mutations causing migraine in terms of phenotype-genotype correlations.
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: JungWook
authors.initials: J
authors.lastname: Park
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: HeuiSoo
authors.initials: H
authors.lastname: Moon
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Akerman
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Holland
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Michele P
authors.initials: MP
authors.lastname: Lasalandra
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Andreou
authors.affiliation: Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
authors.forename: Michel 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 University Medical Centre, 2300 RC Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; NIHR-Wellcome Trust Clinical Research Facility, King's College London, UK. Electronic address: peter.goadsby@kcl.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goadsby
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002524:Cerebellar Ataxia / Q000235:genetics; D004558:Electric Stimulation; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000235:genetics; D020125:Mutation, Missense; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D054063:Superior Sagittal Sinus / Q000187:drug effects / Q000378:metabolism*; D013787:Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism*; D014275:Trigeminal Caudal Nucleus / Q000187:drug effects / Q000378:metabolism; D014278:Trigeminal Nuclei / Q000187:drug effects / Q000378:metabolism*; D014363:Tryptamines / Q000494:pharmacology; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C106783:naratriptan
keywords: Aura; CACNA1A; Familial hemiplegic migraine; Migraine; Trigeminovascular