Department of Cell Biology and Morphology, University of Lausanne, CH-1005 Lausanne, Switzerland.
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13823-8. doi: 10.1073/pnas.1105115108. Epub 2011 Aug 1.
Low-threshold (T-type) Ca(2+) channels encoded by the Ca(V)3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca(V)3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca(V)3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca(V)3.3(-/-) mouse line and demonstrate that Ca(V)3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca(V)3.3 channels prevented oscillatory bursting in the low-frequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca(V)3.1 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(V)3.3(-/-) mice were <30% compared with those in WT mice, and the remaining current, carried by Ca(V)3.2 channels, generated dendritic Ca(2+) signals insufficient to provoke oscillatory bursting that arises from interplay with Ca(2+)-dependent small conductance-type 2 K(+) channels. Finally, naturally sleeping Ca(V)3.3(-/-) 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(V)3.3 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.
低阈值（T 型）钙通道由 Ca(V)3 基因编码，使神经元具有振荡特性，这是构成非快速眼动（NREM）睡眠 EEG 的慢波的基础。三种 Ca(V)3 通道亚型在丘脑皮质（TC）系统中表达，但它们对睡眠 EEG 的各自作用尚不清楚。Ca(V)3.3 蛋白在丘脑网状核（nRt）中大量表达，是一种必不可少的振荡爆发发生器。我们报告了一种转基因 Ca(V)3.3(-/-) 小鼠品系的特征，并证明 Ca(V)3.3 通道对于 nRt 功能和睡眠纺锤波（自然睡眠的标志）是不可或缺的。Ca(V)3.3 通道的缺失阻止了 nRt 细胞中低频（4-10 Hz）范围内的振荡爆发，但保留了紧张放电。相比之下，表达 Ca(V)3.1 通道的相邻 TC 神经元保留了低阈值爆发。然而，由于通过 nRt 细胞对 TC 神经元的抑制减少，睡眠纺锤波下的丘脑网络振荡同步产生明显减弱。与 WT 小鼠相比，Ca(V)3.3(-/-) 小鼠中的 T 电流<30%，而剩余的电流由 Ca(V)3.2 通道携带，产生的树突Ca(2+)信号不足以引发振荡爆发，这种爆发是由与 Ca(2+)-依赖性小电导型 2 K(+) 通道相互作用引起的。最后，自然睡眠的 Ca(V)3.3(-/-) 小鼠在从 NREM 到 REM 睡眠的过渡中，σ 频带（10-12 Hz）的功率密度选择性降低，而其他 EEG 波保持不变。总之，这些数据确定了 Ca(V)3.3 通道在睡眠纺锤波发生器的节律生成特性中的核心作用，并提供了一个分子靶点，以阐明睡眠纺锤波对大脑功能和发育的作用。
