Lessons from Familial Hemiplegic Migraine and Cortical Spreading Depression

Migraine is a common episodic neurological disorder with complex pathophysiology. It is generally recognized that: most migraine attacks start in the brain; migraine headache depends on the activation and sensitization of the trigeminovascular pain pathway; and cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura. Most of the current molecular understanding of migraine comes from studies of familial hemiplegic migraine (FHM), a rare monogenic autosomal dominant form of migraine with aura (MA). This chapter focuses on the physiological role of the proteins encoded by the three known FHM genes and the functional consequences of FHM mutations. It also focuses on the insights into the mechanisms underlying susceptibility to CSD and initiation of migraine attacks obtained from the functional analysis of FHM mouse models. Three different FHM mouse models have been generated by introducing the human FHM1R192Q or S218L and FHM2W887R mutations into the orthologous genes.