Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice

Abstract

Familial hemiplegic migraine type 1 (FHM1), a severe migraine with aura variant, is caused by mutations in the CACNA1A gene. Mutant mice carrying the FHM1 R192Q mutation exhibit increased propensity for cortical spreading depression (CSD), a propagating wave of neuroglial depolarization implicated in migraine aura. The CSD phenotype is stronger in female R192Q mutants and diminishes after ovariectomy. Here, we show that orchiectomy reciprocally increases CSD susceptibility in R192Q mutant mice. Chronic testosterone replacement restores CSD susceptibility by an androgen receptor-dependent mechanism. Hence, androgens modulate genetically-enhanced CSD susceptibility and may provide a novel prophylactic target for migraine.

Figure 1. Androgenic modulation of CSD in R192Q mutant mice

(A) Representative electrophysiological recordings from male wild type (WT) and homozygous R192Q mutant mice showing repetitive CSDs evoked by topical KCl application (300 mM) for 30 min. (B) Graphic representation of CSD frequency and propagation speed in WT and R192Q mutant mice. Naïve R192Q mutant mice developed higher frequency of CSDs compared to WT. Orchiectomy (Orx) further increased CSD frequency in the R192Q mutant, which was restored to the level of naïve R192Q mutants by chronic testosterone replacement (T). The androgen receptor blocker flutamide (F) completely abolished the effects of testosterone replacement. Vertical bar, 20 mV; horizontal bar, 4 min. Data are mean ± standard deviation. *, p<0.001 vs. naïve and Orx+T R192Q mutant. †, p<0.001 vs. WT. Numbers of mice for each group are shown in Table 1.