Familial Hemiplegic Migraine

Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCAA 1A, encoding the pore-forming alpha(1) subunits of the neuronal voltage-gated Ca2+ channels Ca(v)2.1 and Na+ channels Na(v)l.l, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the alpha(2) subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHMI knockin mice and of several FHM mutants in heterologous expression systems (12 FHMI, 8 FHM2, and I FHM3). These studies show the following: (1) FHMI mutations produce gain-of-function of the Ca(v)2.1 channel and, as a consequence, increased Ca(v)2.1 -dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phe-omenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the zeta(2) Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(v)1.5 (and presumably Na(v)1. 1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment