Prefrontal synaptic regulation of homeostatic sleep pressure revealed through synaptic chemogenetics

  • Science. 2024 Sep 27;385(6716):1459-1465. doi: 10.1126/science.adl3043.
Takeshi Sawada  #  1  2 ,  Yusuke Iino  #  3 ,  Kensuke Yoshida  #  3  4 ,  Hitoshi Okazaki  #  1  2 ,  Shinnosuke Nomura  #  3  5 ,  Chika Shimizu  3 ,  Tomoki Arima  1  2  5 ,  Motoki Juichi  3 ,  Siqi Zhou  1 ,  Nobuhiro Kurabayashi  6 ,  Takeshi Sakurai  3  7 ,  Sho Yagishita  1  2 ,  Masashi Yanagisawa  3  8 ,  Taro Toyoizumi  4  9 ,  Haruo Kasai  1  2 ,  Shoi Shi  3
Affiliations
  • 1. International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 2. Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 3. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 4. RIKEN Center for Brain Science, Wako, Saitama, Japan.
  • 5. Department of Physiology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 6. Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
  • 7. Department of Molecular Behavioral Physiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 8. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9. Department of Mathematical Informatics, Graduate School of Information Science and Technology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • # Contributed equally.
PMID: 39325885 DOI: 10.1126/science.adl3043
Abstract

Sleep is regulated by homeostatic processes, yet the biological basis of sleep pressure that accumulates during wakefulness, triggers sleep, and dissipates during sleep remains elusive. We explored a causal relationship between cellular synaptic strength and electroencephalography delta power indicating macro-level sleep pressure by developing a theoretical framework and a molecular tool to manipulate synaptic strength. The mathematical model predicted that increased synaptic strength promotes the neuronal "down state" and raises the delta power. Our molecular tool (synapse-targeted chemically induced translocation of Kalirin-7, SYNCit-K), which induces dendritic spine enlargement and synaptic potentiation through chemically induced translocation of protein Kalirin-7, demonstrated that synaptic potentiation of excitatory neurons in the prefrontal cortex (PFC) increases nonrapid eye movement sleep amounts and delta power. Thus, synaptic strength of PFC excitatory neurons dictates sleep pressure in mammals.