Kinase signalling in excitatory neurons regulates sleep quantity and depth

Staci J. Kim, Noriko Hotta-Hirashima, Fuyuki Asano, Tomohiro Kitazono, Kanako Iwasaki, Shinya Nakata, Haruna Komiya, Nodoka Asama, Taeko Matsuoka, Tomoyuki Fujiyama, Aya Ikkyu, Miyo Kakizaki, Satomi Kanno, Jinhwan Choi, Deependra Kumar, Takumi Tsukamoto, Asmaa Elhosainy, Seiya Mizuno, Shinichi Miyazaki, Yousuke Tsuneoka, Fumihiro Sugiyama, Satoru Takahashi, Yu Hayashi, Masafumi Muratani, Qinghua Liu, Chika Miyoshi, Masashi Yanagisawa () and Hiromasa Funato ()
Additional contact information
Staci J. Kim: University of Tsukuba, Tsukuba
Noriko Hotta-Hirashima: University of Tsukuba, Tsukuba
Fuyuki Asano: University of Tsukuba, Tsukuba
Tomohiro Kitazono: University of Tsukuba, Tsukuba
Kanako Iwasaki: University of Tsukuba, Tsukuba
Shinya Nakata: University of Tsukuba, Tsukuba
Haruna Komiya: University of Tsukuba, Tsukuba
Nodoka Asama: University of Tsukuba, Tsukuba
Taeko Matsuoka: University of Tsukuba, Tsukuba
Tomoyuki Fujiyama: University of Tsukuba, Tsukuba
Aya Ikkyu: University of Tsukuba, Tsukuba
Miyo Kakizaki: University of Tsukuba, Tsukuba
Satomi Kanno: University of Tsukuba, Tsukuba
Jinhwan Choi: University of Tsukuba, Tsukuba
Deependra Kumar: University of Tsukuba, Tsukuba
Takumi Tsukamoto: University of Tsukuba, Tsukuba
Asmaa Elhosainy: University of Tsukuba, Tsukuba
Seiya Mizuno: University of Tsukuba
Shinichi Miyazaki: University of Tsukuba, Tsukuba
Yousuke Tsuneoka: Toho University
Fumihiro Sugiyama: University of Tsukuba
Satoru Takahashi: University of Tsukuba
Yu Hayashi: University of Tsukuba, Tsukuba
Masafumi Muratani: University of Tsukuba
Qinghua Liu: University of Tsukuba, Tsukuba
Chika Miyoshi: University of Tsukuba, Tsukuba
Masashi Yanagisawa: University of Tsukuba, Tsukuba
Hiromasa Funato: University of Tsukuba, Tsukuba

Nature, 2022, vol. 612, issue 7940, 512-518

Abstract: Abstract Progress has been made in the elucidation of sleep and wakefulness regulation at the neurocircuit level1,2. However, the intracellular signalling pathways that regulate sleep and the neuron groups in which these intracellular mechanisms work remain largely unknown. Here, using a forward genetics approach in mice, we identify histone deacetylase 4 (HDAC4) as a sleep-regulating molecule. Haploinsufficiency of Hdac4, a substrate of salt-inducible kinase 3 (SIK3)3, increased sleep. By contrast, mice that lacked SIK3 or its upstream kinase LKB1 in neurons or with a Hdac4S245A mutation that confers resistance to phosphorylation by SIK3 showed decreased sleep. These findings indicate that LKB1–SIK3–HDAC4 constitute a signalling cascade that regulates sleep and wakefulness. We also performed targeted manipulation of SIK3 and HDAC4 in specific neurons and brain regions. This showed that SIK3 signalling in excitatory neurons located in the cerebral cortex and the hypothalamus positively regulates EEG delta power during non-rapid eye movement sleep (NREMS) and NREMS amount, respectively. A subset of transcripts biased towards synaptic functions was commonly regulated in cortical glutamatergic neurons through the expression of a gain-of-function allele of Sik3 and through sleep deprivation. These findings suggest that NREMS quantity and depth are regulated by distinct groups of excitatory neurons through common intracellular signals. This study provides a basis for linking intracellular events and circuit-level mechanisms that control NREMS.

Date: 2022
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DOI: 10.1038/s41586-022-05450-1

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