Loss of <i>Arc</i> attenuates the behavioral and molecular responses for sleep homeostasis in mice

Abstract

The activity-regulated cytoskeleton-associated protein (<i>Arc</i>) 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 <i>Arc</i> in these and other sleep-related processes. However, the role of <i>Arc</i> in sleep remains unknown. Here, we demonstrated that <i>Arc</i> is important for the induction of multiple behavioral and molecular responses associated with sleep homeostasis. <i>Arc</i> 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 <i>Arc</i> 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 <i>GluA1</i> 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. <i>Arc</i> is critical for these behavioral and multiple molecular responses to SD, thus providing a multifunctional role for <i>Arc</i> in the maintenance of sleep homeostasis, which may be attributed by the sleep/wake-associated changes in subcellular location of Arc.