Migraines in Mice?

an allele of tottering that causes profound chronic ataxia associated with pervasive Purkinje and granule cell loss Department of Neuroscience and Anatomy throughout the anterior cerebellum and reduced cere-Pennsylvania State University College of Medicine bellar size. Like tottering mice, spike and wave dis-Hershey, Pennsylvania 17033 charges have been detected in leaner mice, but the paroxysmal convulsions are never observed. Because Recently, the ion channel mutations causing both famil-of the dramatically different phenotypes, tg and tg 1a were ial hemiplegic migraine (FHM) and episodic ataxia type-2 initially characterized as mutations of different genes (EA-2) were identified as defects in the human voltage-(Sidman et al., 1965). However, like FHM and EA-2, ge-dependent calcium channel ␣1A subunit (Ophoff et al., netic linkage and complementation studies demon-1996). Simultaneous with the identification of the FHM/ strated that tg and tg 1a are different alleles of a single EA-2 gene defects, the mutations underlying the tot-genetic locus. tering and leaner mouse phenotypes were identified as Calcium Channel ␣ 1A Subunits defects in the murine voltage-dependent calcium chan-Defects in the voltage-dependent calcium channel ␣ 1A nel ␣ 1A subunit (Fletcher et al., 1996). Because these subunit have been identified in FHM and EA-2 in humans genes are homologs, the mouse mutants tottering and and in tottering and leaner mice. Voltage-dependent leaner may be instrumental in unraveling the pathogene-calcium channels regulate several biologic functions in-sis of FHM and EA-2. cluding neurotransmitter release and excitability by con-Inherited ion channel mutations or " channelopathies " trolling the flux of calcium. These channels are charac-are the cause of several neurologic disorders in humans. terized by voltage-sensitive activation in response to Hypokalemic periodic paralysis, which is characterized depolarization resulting in the selective increase in cal-by intermittent weakness, results from a calcium chan-cium flux into the cell. The channel is then inactivated nel mutation (Ptacek et al., 1994), whereas hyperkalemic and returned to its resting state. The kinetics and voltage periodic paralysis is caused by a sodium channel muta-dependence of activation and inactivation define the tion (Cummins et al., 1993). Episodic ataxia type 1 is specific calcium channel subtype as L, N, P/Q, or R (for produced by a point mutation in a potassium channel Calcium channels are com-ture of these channelopathies is the transient nature of posed of five subunits (␣ 1, ␣2, ␤, ␥, and ␦); however, the neurologic dysfunctions which are characterized by the ␣ 1 subunit alone is sufficient …