Mutations in the human CSNK1D (casein kinase 1, delta) gene have been associated with symptoms of Familial Advanced Sleep Phase Syndrome (FASPS) and migraines. A T44A (threonine to alanine) amino acid mutation disrupts a phosphorylation site, shifts circadian patterns in subjects manifesting as symptoms of early sleep times and early-morning awakening, and predisposes them to migraine.

Hemizygous transgenic mice express 2-3 copies of a full-length, T44A mutant form of the human gene. Under 12 hour light-12 hour dark (LD) and constant darkness (DD) conditions, wild-type transgenic (see Stock No. 022149) and mutant transgenic mice show similar and robust circadian rhythms of wheel-running activity. Free-running periods are significantly shorter in mutant transgenic animals compared with wild-type controls, however. Mutant transgenic mice have a circadian periodicity of 23.42 hours under constant dark conditions compared to 23.78 hours in wildtype controls. They also take significantly longer to re-entrain to a light-dark regime after two weeks of constant darkness.

Treatment of mutant transgenic mice with nitroglycerin (NTG) evokes peripheral mechanical and thermal hyperalgesia. Mechanical thresholds are significantly lower in the T44A mice than in wildtype controls, in a migraine-like phenotype. Mice are also more sensitive to thermal stimuli than wildtype siblings, with a significantly lower recovery from thermal hyperalgesia. Ninety minutes after NTG treatment (5 mg/kg, i.p.), females, but not males, show a significant reduction in latency to paw withdrawal from a heat source compared to wildtype. Transgenic mutant animals exhibit lower thresholds to induce cortical spreading depression (a wave of ionic disturbance thought to be similar to migraine aura) during which their arteries are abnormally dilated, as seen during migraine in humans.