Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice.
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.
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
Katharina
K
Eikermann-Haerter
Michael J
MJ
Baum
Michel D
MD
Ferrari
Arn M J M
AM
van den Maagdenberg
Michael A
MA
Moskowitz
Cenk
C
Ayata
D000818:Animals; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics; D013181:Cortical Spreading Depression / Q000235:genetics*; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020325:Migraine with Aura / Q000235:genetics* / Q000378:metabolism*; D009919:Orchiectomy; D017354:Point Mutation; D013739:Testosterone / Q000235:genetics* / Q000502:physiology; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D013739:Testosterone; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type