Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need
Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need
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DOI：
10.1523/jneurosci.1004-20.2020
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发表时间：
2021-03-24
影响因子：
5.3
通讯作者：
Yanagisawa, Masashi
中科院分区：
文献类型：
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作者：
Iwasaki, Kanako;Fujiyama, Tomoyuki;Yanagisawa, Masashi
睡眠以体内平衡的方式调节。睡眠不足会增加睡眠需求，这主要通过非快速眼动睡眠 (NREMS) 期间脑电图增量功率的增加以及在较小程度上通过睡眠量的增加来补偿。尽管遗传因素决定了小鼠和人类的睡眠需求和睡眠量的构成水平，但睡眠需求背后的分子实体仍然未知。最近，我们发现盐诱导激酶 3 (Sik3) 基因中的功能获得性 Sleepy (Slp) 突变会产生突变型 SIK3(SLP) 蛋白，导致 NREMS 脑电图 delta 功率和睡眠量增加。由于Sik3(Slp)小鼠从胚胎阶段起就在大脑的各种类型的细胞以及多种外周组织中表达SIK3(SLP)，因此导致Sik3(Slp)小鼠睡眠表型的细胞类型和发育阶段仍有待阐明。在这里，我们生成了两个小鼠品系：突触蛋白 1 (CreERT2) 和 Sik3 (ex13flox) 小鼠，它们能够在给予他莫昔芬时在神经元中诱导 Cre 介导的 SIK3 (SLP) 条件表达。在婴儿期晚期对突触蛋白1（CreERT2）小鼠施用他莫昔芬比在青春期施用他莫昔芬产生更高的重组效率。婴儿后期 SIK3（SLP）的表达增加了雄性突触蛋白 1（CreERT2）的 NREMS 和 NREMS δ 功率； Sik3(ex13flox/+) 小鼠。青春期后 SIK3(SLP) 的表达导致 NREMS 增量功率更高，而 NREMS 量没有显着变化。因此，婴儿晚期后 SIK3(SLP) 的神经元特异性表达足以增加睡眠。
Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG delta power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy (Slp) mutation in the salt-inducible kinase 3 (Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG delta power and sleep amount. Since Sik3(Slp) mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3(Slp) mice remain to be elucidated. Here, we generated two mouse lines, synapsin1(CreERT2) and Sik3(ex13flox) mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1(CreERT2) mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS delta power in male synapsin1(CreERT2); Sik3(ex13flox/+) mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS delta power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.