The Ca _v3.3 calcium channel is the major sleep spindle pacemaker in thalamus

Low-threshold (T-type) Ca ²⁺ channels encoded by the Ca _V3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca _V3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca _V3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca _V3.3 ^-/- mouse line and demonstrate that Ca _V3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca _V3.3 channels prevented oscillatory bursting in the lowfrequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca _V3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca _V3.3 ^-/- mice were <30% compared with those in WT mice, and the remaining current, carried by Ca _V3.2 channels, generated dendritic [Ca ²⁺] _i signals insufficient to provoke oscillatory bursting that arises from interplay with Ca ²⁺-dependent small conductance-type 2 K ⁺ channels. Finally, naturally sleeping Ca _V3.3 ^-/- mice showed a selective reduction in the power density of the σ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca _V3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.