Advances in molecular, genetic, and cell biological techniques have allowed neuroscientists to delve into the cellular machinery of learning and memory. The calcium and calmodulin-dependent kinase type II (CaMKII) is one of the best candidates for being a molecular component of the learning and memory machinery in the mammalian brain. It is present in abundance at synapses and its enzymatic properties and responsiveness to intracellular Ca2+ fit a model whereby Ca2+ currents activate the kinase and lead to changes in (...) synaptic efficacy. Indeed, such plastic properties of synapses are thought to be important for memory formation. Genetic analysis of the alpha isoform of CaMKII in mice support the hypothesis that CaMKII signaling is required to initiate the formation of new spatial memories in the hippocampus. CaMKII is also required for the correct induction of long-term potentiation (LTP) in the hippocampus, consistent with the widely held belief that LTP is a mechanism for learning and memory. Recent cell biological, genetic, and physiological analyses suggest that one of the cellular explanations for LTP and CaMKII function might be the trafficking of AMPA-type receptors to synapses in response to neural activity. BioEssays 24:223–233, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10057. (shrink)

Although we are beginning to understand the neuronal and biochemical nature of sleep regulation, questions remain about how sleep is homeostatically regulated. Beyond its importance in basic physiology, understanding sleep may also shed light on psychiatric and neurodevelopmental disorders. Recent genetic studies in mammals revealed several non-secretory proteins that determine sleep duration. Interestingly, genes identified in these studies are closely related to psychiatric and neurodevelopmental disorders, suggesting that the sleep-wake cycle shares some common mechanisms with these disorders. Here we review (...) recent sleep studies, including reverse and forward genetic studies, from the perspectives of sleep duration and homeostasis. We then introduce a recent hypothesis for mammalian sleep in which the fast and slow Ca2+-dependent hyperpolarization pathways are pivotal in generating the SWS firing pattern and regulating sleep homeostasis, respectively. Finally, we propose that these intracellular pathways are potential therapeutic targets for achieving depolarization/hyperpolarization balance in psychiatric and neurodevelopmental disorders. How animals implement sleep homeostasis is a great mystery. Here, we review recent studies with highlighting the hypothesis that the slow Ca2+-dependent hyperpolarization pathway regulates sleep homeostasis via modifying the fast pathway; the activity of CaMKIIα/β increases during wakefulness, which triggers sleep by phosphorylating the components in the fast pathway. (shrink)

Sleep is a fundamental property conserved across species. The homeostatic induction of sleep indicates the presence of a mechanism that is progressively activated by the awake state and that induces sleep. Several lines of evidence support that such function, namely, sleep need, lies in the neuronal assemblies rather than specific brain regions and circuits. However, the molecular mechanism underlying the dynamics of sleep need is still unclear. This review aims to summarize recent studies mainly in rodents indicating that protein phosphorylation, (...) especially at the synapses, could be the molecular entity associated with sleep need. Genetic studies in rodents have identified a set of kinases that promote sleep. The activity of sleep-promoting kinases appears to be elevated during the awake phase and in sleep deprivation. Furthermore, the proteomic analysis demonstrated that the phosphorylation status of synaptic protein is controlled by the sleep-wake cycle. Therefore, a plausible scenario may be that the awake-dependent activation of kinases modifies the phosphorylation status of synaptic proteins to promote sleep. We also discuss the possible importance of multisite phosphorylation on macromolecular protein complexes to achieve the slow dynamics and physiological functions of sleep in mammals. (shrink)