Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice

Objective: Mammalian circadian rhythms are driven by the circadian pacemaker of the suprachiasmatic nucleus (SCN) and are synchronized to the external 24-hour light/dark cycle. After advance time zone transitions (eastbound jet lag), overt circadian rhythms require several days to adjust. The retarded adaptation may protect against acute imbalance of different brain systems. Abrupt circadian rhythm changes may trigger migraine attacks, possibly because migraineurs have an inadequate adaptation mechanism. The novel R192Q knock-in migraine mouse model carries mutated Cav2.1 calcium channels, causing increased presynaptic calcium influx and neurotransmitter release. We investigated whether these mice have an abnormal adjustment to phase advance shifts. Methods: We examined phase resetting to 6-hour advance shifts of the light/dark cycle with behavioral and electroencephalographic recordings in R192Q and wild-type mice. We recorded excitatory postsynaptic currents in the SCN, and electrical impulse frequency in vitro and in vivo. Results: R192Q mice showed a more than twofold enhanced adjustment of behavioral wheel-running activity and electroencephalographic patterns, as well as enhanced shifts of electrical activity of SCN neurons in vivo. No differences were found for in vitro recordings of the electrical impulse frequency in SCN slices. Interpretation: R192Q migraine mice lack the physiological retardation in circadian adaptation to phase advance shifts. The opposite findings in vivo and in vitro exclude involvement of the retinal input pathway or the phase-shifting capacity of the SCN. Thus, the physiological inhibitory process appears to be mediated by Cav2.1 channel–dependent afferent signaling from extra-SCN brain areas to the SCN. Ann Neurol 2008;64:315–324 Mammalian circadian rhythms in physiology and behavior are driven by a master pacemaker within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Individual neurons of the SCN are intrinsically capable of generating a circadian rhythm. 1 To entrain to the environmental light/dark (LD) cycle, light information is conveyed from specialized retinal photoreceptors to the SCN through the retinohypothalamic tract, 2 which utilizes glutamate and pituitary adenylate cyclase-activating peptide as its major neurotransmitters. 3,4 After a shift of the LD cycle, as in