CAV1.2 calcium channel is involved in the circadian regulation of sleep

Abstract

Two L-type Ca 2+ channels (Cav1.2 & Cav1.3) are expressed in the mouse brain with Cav1.2 contributing to a major proportion (85%). The expression of L-type Ca 2+ channels is greatly densed in the suprachiasmatic nuclei, a neuronal area capable of functioning as autonomous clock and as a generator of circadian rhythms. Although one of the most important aspects regarding the circadian rhythm is the sleep–wake cycle, yet the role of Cav1.2 in the sleep–wake cycle is unclear. Therefore, we investigated whether depletion of Cav1.2 in a transgenic mouse line Cav1.2 (+/−) would alter spontaneous sleep–wake activities. Sleep–wake patterns were monitored by means of EEG and EMG recordings in Cav1.2 (+/−) mice and their wild-type littermates under baseline and sleep deprivation conditions (6 h by gentle handling). Under basal condition, Cav1.2 (+/−) mice showed increased sleep onset latency but subsequent hypersomnolence as compared to wild-type. The hypersomnolence observed in these mice was characterized by higher slow wave activity. Moreover, these heterozygous mice also exhibited drastically shorter wake episodes in the dark period, due to an increased number of NREM sleep episodes. Analysis of sleep architecture further revealed that these mice showed frequent transitions from wake to NREM sleep and vice versa. After sleep deprivation, the sleep onset latency decreased drastically and the trend for higher NREM sleep was observed in Cav1.2 (+/−) mice. Our results demonstrate that depletion of Cav1.2 significantly impacts circadian sleep regulation indicated by increased NREM sleep and decreased time spent in wake in the dark period. However, homeostatic regulation of sleep was unaltered. It has been reported that L-type Ca 2+ channels are involved in wake-promoting effects of hypocretin1. Therefore, decreased wakefulness in Cav1.2 (+/−) mice suggests that a depletion of Cav1.2 might attenuate the hypocretin 1 mediated excitation of wake-related neurons. The alpha-1 subunit of L-type Ca 2+ channels (Cav1.2) is encoded by the CACNA1C gene. Genome-wide association studies (GWAS) have suggested that polymorphisms in the CACNA1C gene are associated with sleep disorders, e.g., insomnia and narcolepsy. Increased sleep onset latency and fragmented sleep architecture displayed by Cav1.2 (+/−) mice might be signs of symptomatic sleep disorders but further studies are needed to elucidate this. Nevertheless, several GWAS studies have significantly associated the CACNA1C gene with psychiatric disorders.