TY - JOUR
T1 - Loss of Arc attenuates the behavioral and molecular responses for sleep homeostasis in mice
AU - Suzuki, Ayako
AU - Yanagisawa, Masashi
AU - Greene, Robert W.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Kimberly Huber (UT Southwestern Medical Center) for providing Arc KO mouse breeding pairs. This work was supported by National Institute of Neurological Disorders and Stroke (R01NS103422-01), and Veterans Affairs (1I01BX002646-01A2) (to R.W.G.); Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) 26220207 and 17H06095; Japan Science and Technology Agency (JST) Core Research for Evolutionary Science and Technology (CREST) Grant JPMJCR1655; Funding Program for World-Leading Innovative R&D on Science & Technology (FIRST) program from JSPS; the Uehara and Takeda Foundations; and the World Premier International Research Center Initiative program from Japan’s Ministry of Education, Culture, Sports, Science, and Technology (to M.Y.).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/5/12
Y1 - 2020/5/12
N2 - The activity-regulated cytoskeleton-associated protein (Arc) gene is a neural immediate early gene that is involved in synaptic downscaling and is robustly induced by prolonged wakefulness in rodent brains. Converging evidence has led to the hypothesis that wakefulness potentiates, and sleep reduces, synaptic strengthening. This suggests a potential role for Arc in these and other sleep-related processes. However, the role of Arc in sleep remains unknown. Here, we demonstrated that Arc is important for the induction of multiple behavioral and molecular responses associated with sleep homeostasis. Arc knockout (KO) mice displayed increased time spent in rapid eye movement (REM) sleep under baseline conditions and marked attenuation of sleep rebound to both 4 h of total sleep deprivation (SD) and selective REM deprivation. At the molecular level, the following homeostatic sleep responses to 4-h SD were all blunted in Arc KO mice: Increase of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 and its phosphorylation in synaptoneurosomes; induction of a subset of SD-response genes; and suppression of the GluA1 messenger RNA in the cortex. In wild-type brains, SD increased Arc protein expression in multiple subcellular locations, including the nucleus, cytoplasm, and synapse, which is reversed in part by recovery sleep. Arc is critical for these behavioral and multiple molecular responses to SD, thus providing a multifunctional role for Arc in the maintenance of sleep homeostasis, which may be attributed by the sleep/wake-associated changes in subcellular location of Arc.
AB - The activity-regulated cytoskeleton-associated protein (Arc) gene is a neural immediate early gene that is involved in synaptic downscaling and is robustly induced by prolonged wakefulness in rodent brains. Converging evidence has led to the hypothesis that wakefulness potentiates, and sleep reduces, synaptic strengthening. This suggests a potential role for Arc in these and other sleep-related processes. However, the role of Arc in sleep remains unknown. Here, we demonstrated that Arc is important for the induction of multiple behavioral and molecular responses associated with sleep homeostasis. Arc knockout (KO) mice displayed increased time spent in rapid eye movement (REM) sleep under baseline conditions and marked attenuation of sleep rebound to both 4 h of total sleep deprivation (SD) and selective REM deprivation. At the molecular level, the following homeostatic sleep responses to 4-h SD were all blunted in Arc KO mice: Increase of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 and its phosphorylation in synaptoneurosomes; induction of a subset of SD-response genes; and suppression of the GluA1 messenger RNA in the cortex. In wild-type brains, SD increased Arc protein expression in multiple subcellular locations, including the nucleus, cytoplasm, and synapse, which is reversed in part by recovery sleep. Arc is critical for these behavioral and multiple molecular responses to SD, thus providing a multifunctional role for Arc in the maintenance of sleep homeostasis, which may be attributed by the sleep/wake-associated changes in subcellular location of Arc.
KW - Activity-regulated cytoskeletonassociated protein
KW - GluA1
KW - Immediate early gene
KW - Nuclear translocation
KW - Sleep homeostasis
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U2 - 10.1073/pnas.1906840117
DO - 10.1073/pnas.1906840117
M3 - Article
C2 - 32350140
AN - SCOPUS:85084585978
SN - 0027-8424
VL - 117
SP - 10547
EP - 10553
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -