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Enhanced circadian phase resetting in R192Q Ca v 2.1 calcium channel migraine mice
Author(s) -
van Oosterhout Floor,
Michel Stephan,
Deboer Tom,
Houben Thijs,
van de Ven Rob C. G.,
Albus Henk,
Westerhout Joost,
Vansteensel Mariska J.,
Ferrari Michel D.,
van den Maagdenberg Arn M. J. M.,
Meijer Johanna H.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21418
Subject(s) - circadian rhythm , light effects on circadian rhythm , neuroscience , excitatory postsynaptic potential , calcium channel , suprachiasmatic nucleus , inhibitory postsynaptic potential , postsynaptic potential , biology , voltage dependent calcium channel , rhythm , medicine , endocrinology , circadian clock , calcium , receptor
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 Ca v 2.1 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 Ca v 2.1 channel–dependent afferent signaling from extra‐SCN brain areas to the SCN. Ann Neurol 2008;64:315–324