Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1
Katharina Eikermann-Haerter, … , Michael A. Moskowitz, Cenk Ayata
Katharina Eikermann-Haerter, … , Michael A. Moskowitz, Cenk Ayata
Published December 22, 2008
Citation Information: J Clin Invest. 2009;119(1):99-109. https://doi.org/10.1172/JCI36059.
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Research Article

Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1

Abstract

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the α1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

Authors

Katharina Eikermann-Haerter, Ergin Dileköz, Chiho Kudo, Sean I. Savitz, Christian Waeber, Michael J. Baum, Michel D. Ferrari, Arn M.J.M. van den Maagdenberg, Michael A. Moskowitz, Cenk Ayata

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Figure 1

Enhanced CSD susceptibility in FHM1 mutant mice.

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Enhanced CSD susceptibility in FHM1 mutant mice. (A) Representative elec...
(A) Representative electrophysiological recordings showing increased frequency of slow (DC) potential shifts during repetitive CSDs in male and female homozygous R192Q or S218L mutants compared with WT mice evoked by topical KCl application (300 mM) for 30 minutes. The number of CSDs was substantially higher in FHM1 mutant strains compared with WT controls and in female mutants versus males. Calibration bars: vertical, 20 mV; horizontal, 10 minutes. (B) The impact of R192Q and S218L mutations, allele dosage, and sex on CSD frequency and propagation speed (upper and lower graphs, respectively). Higher CSD frequencies and propagation speeds were found in both FHM1 mutants, with values higher in S218L than in R192Q mutants and an allele dosage relation. CSD frequency was greater and propagation faster in females compared with males in both FHM1 mutant strains. No sex difference was found in WT mice. Covariance analysis revealed that 82% of variation in CSD frequency and 93% of variation in CSD propagation speed were explained by the independent variables mutation, genotype, and sex (see Methods). Numbers of mice per group are shown within the bars. HET, heterozygous; HOM, homozygous. Data are mean ± standard deviation. **P < 0.001, *P < 0.01 versus male in CSD frequency and propagation speed; †P < 0.001 versus WT and homozygous mutant; ‡P < 0.001 versus WT and heterozygous mutant; §P < 0.001 versus corresponding R192Q genotype.