Cacna1c (Cav1.2) modulates electroencephalographic rhythm and rapid eye movement sleep recovery

Abstract

Study Objectives: The CACNA1C gene encodes the alpha 1C (α1C) subunit of the Cav1.2 voltage-dependent L-type calcium channel (LTCC). Some of the other voltage-dependent calcium channels, e.g., P-/Q-type, Cav2.1; N-type, Cav2.2; E-/R-type, Cav2.3; and T-type, Cav3.3 have been implicated in sleep modulation. However, the contribution of LTCCs to sleep remains largely unknown. Based on recent genome-wide association studies, CACNA1C emerged as one of potential candidate genes associated with both sleep and psychiatric disorders. Indeed, most patients with mental illnesses have sleep problems and vice versa. Design: To investigate an impact of Cav1.2 on sleep-wake behavior and electroencephalogram (EEG) activity, polysomnography was performed in heterozygous Cacna1c (HET) knockout mice and their wild-type (WT) littermates under baseline and challenging conditions (acute sleep deprivation and restraint stress). Measurements and Results: HET mice displayed significantly lower EEG spectral power than WT mice across high frequency ranges (beta to gamma) during wake and rapid eye movement (REM) sleep. Although HET mice spent slightly more time asleep in the dark period, daily amounts of sleep did not differ between the two genotypes. However, recovery sleep after exposure to both types of challenging stress conditions differed markedly; HET mice exhibited reduced REM sleep recovery responses compared to WT mice. Conclusions: These results suggest the involvement of Cacna1c (Cav1.2) in fast electroencephalogram oscillations and REM sleep regulatory processes. Lower spectral gamma activity, slightly increased sleep demands, and altered REM sleep responses found in heterozygous Cacna1c knockout mice may rather resemble a sleep phenotype observed in schizophrenia patients.