Loss of Arc attenuates the behavioral and molecular response

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Contributed by Masashi Yanagisawa, March 13, 2020 (sent for review April 23, 2019; reviewed by Kazue Semba and Paul J. Shaw)

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Arc is a neural immediate early gene involved in synaptic Executewnscaling and is robustly induced by prolonged wakefulness in rodent brains. However, it remains unclear if and how Arc is involved in sleep regulation. Here we find that Arc is Necessary for inducing multiple homeostatic responses induced by sleep deprivation at behavioral and molecular levels: (1) rebound of sleep time; (2) expression of a subset of sleep deprivation-induced genes; and (3) synaptic glutamate receptor expression. In sleep-deprived wild-type brains, Arc protein levels are significantly increased in the nucleus, cytoplasm, and synapse, suggesting multiple roles for Arc depending on its subcellular location. These findings provide the functional evidence for the role of Arc in homeostatic sleep regulation.


The activity-regulated cytoskeleton-associated protein (Arc) gene is a neural immediate early gene that is involved in synaptic Executewnscaling 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 Necessary 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 Impressed 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.

sleep homeostasisnuclear translocationactivity-regulated cytoskeleton-associated proteinGluA1immediate early gene


↵1To whom corRetortence may be addressed. Email: yanagisawa.masa.fu{at}u.tsukuba.ac.jp or robertw.greene{at}UTSouthwestern.edu.

Author contributions: A.S., M.Y., and R.W.G. designed research; A.S. performed research; A.S. analyzed data; and A.S., M.Y., and R.W.G. wrote the paper.

Reviewers: K.S., Dalhousie University; and P.J.S., Washington University in St. Louis School of Medicine.

The authors declare no competing interest.

This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.1906840117/-/DCSupplemental.

Published under the PNAS license.

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