N-type calcium channel alpha1B subunit (Cav2.2) knock-out mice display hyperactivity and vigilance state differences

Abstract

Differential properties of voltage-dependent Ca2+ channels have been primarily ascribed to the alpha1 subunit, of which 10 different subtypes are currently known. For example, channels that conduct the N-type Ca2+ current possess the alpha1B subunit (Cav2.2), which has been localized, inter alia, to the piriform cortex, hippocampus, hypothalamus, locus coeruleus, dorsal raphe, thalamic nuclei, and granular layer of the cortex. Some of these regions have been previously implicated in metabolic and vigilance state control, and selective block of the N-type Ca2+ channel causes circadian rhythm disruption. In this study of Cav2.2-/- knock-out mice, we examined potential differences in feeding behavior, spontaneous locomotion, and the sleep-wake cycle. Cav2.2-/- mice did not display an overt metabolic phenotype but were hyperactive, demonstrating a 20% increase in activity under novel conditions and a 95% increase in activity under habituated conditions during the dark phase, compared with wild-type littermates. Cav2.2-/- mice also displayed vigilance state differences during the light phase, including increased consolidation of rapid-eye movement (REM) sleep and increased intervals between non-REM (NREM) and wakefulness episodes. EEG spectral power was increased during wakefulness and REM sleep and was decreased during NREM sleep in Cav2.2-/- mice. These results indicate a role of the N-type Ca2+ channel in activity and vigilance state control, which we interpret in terms of effects on neurotransmitter release.

Figure 1.

Spontaneous locomotor activity in Ca_v2.2^-/- mice and Ca_v2.2^+/+ wild-type littermates. Activity counts (mean ± SEM) were determined under novel conditions for 12 min during the light phase (n = 8 per genotype) and under habituated conditions for 3 consecutive days (n = 6 per genotype). Significant differences are indicated by one asterisk (p < 0.05) or two asterisks (p < 0.01).

Figure 2.

EEG power spectra for Ca_v2.2^-/- mice (n = 6; dashed lines) and Ca_v2.2^+/+ littermates (n = 6; solid lines). Spectra were extracted from selected epochs and normalized to the average signal strength of each individual animal before being averaged over all animals of the respective genotype. A-C, Spectra itemized separately for light (gray) and dark (black) phases. A, Wakefulness. B, NREM sleep. C, REM sleep. Note that spectral power for wakefulness and REM sleep is increased in Ca_v2.2^-/- mice, but it is decreased during NREM sleep in this genotype. REM sleep and NREM sleep spectra of the Ca_v2.2^-/- mice also show a shift in the peak frequency of approximately -1 Hz.