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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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 5

Facilitated corticostriatal SD propagation in FHM1 mutant mice.

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Facilitated corticostriatal SD propagation in FHM1 mutant mice. (A) Repr...
(A) Representative extracellular DC potential shifts recorded simultaneously from cortex and striatum in female WT and homozygous R192Q and S218L mutant mice. SD was not observed to propagate into the striatum in any of the WT mice. A substantial proportion of CSDs propagated into the striatum in R192Q and to a greater extent in the S218L mutant. Calibration bars: vertical, 20 mV; horizontal, 10 minutes. (B) The frequency of SDs during continuous topical KCl application (300 mM) to the occipital cortex. CSD frequency (gray bars) was substantially higher in S218L and to a lesser extent in R192Q mutant mice than WT. They were higher in females compared with males and homozygous FHM1 mutants compared with heterozygotes (see Figure 1). CSDs readily propagated into striatum (black bars) in both FHM1 mutant strains, but never in the WT. Striatal propagation was more frequent in S218L (lower graphs) compared with R192Q mutants (upper graphs) and in females (right) compared with males (left), with an allele dosage relation (see Table 2 for latencies between cortical and striatal SDs). Covariance analysis revealed that 83% of the variance of striatal SD frequency was explained by the independent variables mutation, genotype, and sex (see Methods). n = 3–8 mice per group as shown within each bar. Data are mean ± standard deviation. *P < 0.01 versus male; †P < 0.001, §P < 0.05 versus heterozygous mutants; ‡P < 0.01 versus R192Q males.