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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
J Clin Invest. 2009;
119(1):99
doi:10.1172/JCI36059
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F
amilial 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.
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