Episodic Ataxia type 2 (EA2), caused by mutations in the CACNA1A gene, results in a loss-of-function of the P/Q type calcium channel, which leads to baseline ataxia, and attacks of dyskinesia, that can last a few hours to a few days. Attacks are brought on by consumption of caffeine, alcohol, and physical or emotional stress. Interestingly, caffeine and stress are common triggers among other episodic channelopathies, as well as causing tremor or shaking in otherwise healthy adults. The mechanism underlying stress and caffeine induced motor impairment remains poorly understood. Utilizing behavior, and in vivo and in vitro electrophysiology in the tottering mouse, a well characterized mouse model of EA2, or WT mice, we first sought to elucidate the mechanism underlying stress-induced motor impairment. We found stress induces attacks in EA2 though the activation of cerebellar alpha 1 adrenergic receptors by norepinephrine (NE) through casein kinase 2 (CK2) dependent phosphorylation. This decreases SK2 channel activity, causing increased Purkinje cell irregularity and motor impairment. Knocking down or blocking CK2 with an FDA approved drug CX-4945 prevented PC irregularity and stress-induced attacks. We next hypothesized caffeine, which has been shown to increase NE levels, could induce attacks through the same alpha 1 adrenergic mechanism in EA2. We found caffeine increases PC irregularity and induces attacks through the same CK2 pathway. Block of alpha 1 adrenergic receptors, however, failed to prevent caffeine-induced attacks. Caffeine instead induces attacks through the block of cerebellar A1 adenosine receptors. This increases the release of glutamate, which interacts with mGluR1 receptors on PC, resulting in erratic firing and motor attacks. Finally, we show a novel direct interaction between mGluR1 and CK2, and inhibition of mGluR1 prior to initiation of attack, prevents the caffeine-induced increase in phosphorylation. These data elucidate the mechanism underlying stress and caffeine-induced motor impairment. Furthermore, given the success of CX-4945 to prevent stress and caffeine induced attacks, it establishes ground-work for the development of therapeutics for the treatment of caffeine and stress induced attacks in EA2 patients and possibly other episodic channelopathies.

Daily caffeine consumption and chronic sleep restriction are highly prevalent in society. It is well established that acute caffeine intake under controlled conditions enhances vigilance and promotes wakefulness but can also delay sleep initiation and reduce electroencephalographic (EEG) markers of sleep intensity, particularly in susceptible individuals. To investigate whether these effects are also present during chronic consumption of coffee/caffeine, we recently conducted several complementary studies. We examined whether repeated coffee intake in dose and timing mimicking ‘real world’ habits maintains simple and complex attentional processes during chronic sleep restriction, such as during a busy work week. We found in genetically caffeine-sensitive individuals that regular coffee (300 mg caffeine/day) benefits most attentional tasks for 3-4 days when compared to decaffeinated coffee. Genetic variants were also used in the population-based HypnoLaus cohort, to investigate whether habitual caffeine consumption causally affects time to fall asleep, number of awakenings during sleep, and EEG-derived sleep intensity. The multi-level statistical analyses consistently showed that sleep quality was virtually unaffected when >3 caffeine-containing beverages/day were compared to 0-3 beverages/day. This conclusion was further corroborated by quantifying the sleep EEG in the laboratory in habitual caffeine consumers. Compared to placebo, daily intake of 3 x 150 mg caffeine over 10 days did not strongly impair nocturnal sleep nor subjective sleep quality in good sleepers. Finally, we tested whether an engineered delayed, pulsatile-release caffeine formula can improve the quality of morning awakening in sleep-restricted volunteers. We found that 160 mg caffeine taken at bedtime ameliorated the quality of awakening, increased positive and reduced negative affect scores, and promoted sustained attention immediately upon scheduled wake-up. Such an approach could prevent over-night caffeine withdrawal and provide a proactive strategy to attenuate disabling sleep inertia. Taken together, the studies suggest that common coffee/caffeine intake habits can transiently attenuate detrimental consequences of reduced sleep virtually without disturbing subjective and objective markers of sleep quality. Nevertheless, coffee/caffeine consumption cannot compensate for chronic sleep restriction.