Induction of mutant Sik3sleepyallele in neurons in late infancy increases sleep need

Kanako Iwasaki, Tomoyuki Fujiyama, Shinya Nakata, Minjeong Park, Chika Miyoshi, Noriko Hotta-Hirashima, Aya Ikkyu, Miyo Kakizaki, Fumihiro Sugiyama, Seiya Mizuno, Manabu Abe, Kenji Sakimura, Satoru Takahashi, Hiromasa Funato, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ 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 δ power and sleep amount. Since Sik3Slp 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 Sik3Slp mice remain to be elucidated. Here, we generated two mouse lines, synapsin1CreERT2 and Sik3ex13flox mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1CreERT2 mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in male synapsin1CreERT2; Sik3ex13flox/+ mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.

Original languageEnglish (US)
Pages (from-to)2733-2746
Number of pages14
JournalJournal of Neuroscience
Issue number12
StatePublished - Mar 24 2021


  • Kinase
  • SIK3
  • Sleep

ASJC Scopus subject areas

  • General Neuroscience


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