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 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.


CONCLUSIONS
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.
van Oosterhout
Floor
F
Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
Michel
Stephan
S
Deboer
Tom
T
Houben
Thijs
T
van de Ven
Rob C G
RC
Albus
Henk
H
Westerhout
Joost
J
Vansteensel
Mariska J
MJ
Ferrari
Michel D
MD
van den Maagdenberg
Arn M J M
AM
Meijer
Johanna H
JH
D000200:Action Potentials / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D020864:Calcium Channels, N-Type / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D004195:Disease Models, Animal; D004569:Electroencephalography; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D012160:Retina / Q000502:physiology; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000503:physiopathology
D020864:Calcium Channels, N-Type