TY - JOUR
T1 - Induction of mutant Sik3sleepyallele in neurons in late infancy increases sleep need
AU - Iwasaki, Kanako
AU - Fujiyama, Tomoyuki
AU - Nakata, Shinya
AU - Park, Minjeong
AU - Miyoshi, Chika
AU - Hotta-Hirashima, Noriko
AU - Ikkyu, Aya
AU - Kakizaki, Miyo
AU - Sugiyama, Fumihiro
AU - Mizuno, Seiya
AU - Abe, Manabu
AU - Sakimura, Kenji
AU - Takahashi, Satoru
AU - Funato, Hiromasa
AU - Yanagisawa, Masashi
N1 - Funding Information:
This work was supported by Ministry of Education, Culture, Sports, Science and Technology World Premier International Research Center Initiative to M.Y.; Japan Society for the Promotion of Science KAKENHI (17H06095 to M.Y. and H.F.; 16K15187, 17H04023, 17H05583, and 20H00567 to H.F.; 26507003 and 18968064 to C.M. and H.F.;20J12137 to K.I.; 15J00393 and 18K14811 to T.F.); Ministry of Education, Culture, Sports, Science and Technology KEKENHI (15K21745 to H.F.); Japan Society for the Promotion of Science Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) to M.Y.; and Uehara Memorial Foundation, Naito Foundation, and Astellas Foundation for Research on Metabolic Disorders to H.F. We thank Yanagisawa/Funato laboratory members and International Institute for Integrative Sleep Medicine members for the kind support, technical assistance, and discussion.
Funding Information:
This work was supported by Ministry of Education, Culture, Sports, Science and Technology World Premier International Research Center Initiative to M.Y.; Japan Society for the Promotion of Science KAKENHI (17H06095 to M.Y. and H.F.; 16K15187, 17H04023, 17H05583, and 20H00567 to H.F.; 26507003 and 18968064 to C.M. and H.F.;20J12137 to K.I.; 15J00393 and 18K14811 to T.F.); Ministry of Education, Culture, Sports, Science and Technology KEKENHI (15K21745 to H.F.); Japan Society for the Promotion of Science Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) to M.Y.; and Uehara Memorial Foundation, Naito Foundation, and Astellas Foundation for Research on Metabolic Disorders to H.F. We thank Yanagisawa/Funato laboratory members and International Institute for Integrative Sleep Medicine members for the kind support, technical assistance, and discussion. The authors declare no competing financial interests.
Publisher Copyright:
Copyright © 2021 the authors.
PY - 2021/3/24
Y1 - 2021/3/24
N2 - 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.
AB - 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.
KW - Kinase
KW - SIK3
KW - Sleep
UR - http://www.scopus.com/inward/record.url?scp=85103055809&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103055809&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1004-20.2020
DO - 10.1523/JNEUROSCI.1004-20.2020
M3 - Article
C2 - 33558433
AN - SCOPUS:85103055809
SN - 0270-6474
VL - 41
SP - 2733
EP - 2746
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 12
ER -