Ca²⁺‐Dependent Hyperpolarization Pathways in Sleep Homeostasis and Mental Disorders

Abstract

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 Ca 2þ -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 (D/H) balance in psychiatric and neurodevelopmental disorders.

The bidirectional causal relationships of insomnia with five major psychiatric disorders: A Mendelian randomization study

“…An inferior sleep status, including insomnia, may cause imbalances between the internal and external environment, eventually increasing the risk of developing psychiatric disorders [11]. Previous studies have indicated that regulating sleep via related intracellular pathways may achieve a balance in neural excitability for patients with psychiatric disorders [51].…”

Leak potassium channels regulate sleep duration

“…Ca 2+ -dependent K + channels cooperatively induce the down state, and hence the SWS firing pattern. According to the AN model (13,14,23,24), the putative intracellular mechanism for generating the SWS firing pattern is as follows (Fig. 4I).…”

Molecular Mechanisms of REM Sleep

“…Because the Ca 2+ -dependent hyperpolarization pathway plays an important role in switching UP and DOWN states of neurons (Tatsuki et al, 2016(Tatsuki et al, , 2017, and the persistent UP state is associated with wakefulness, Ca 2+ -dependent phosphorylation is a promising regulatory component for the homeostasis in sleep and wake cycle (Ode et al, 2017;Shi and Ueda, 2018). A candidate gene family to be involved in Ca 2+ -dependent phosphorylation is calcium/CaMKII.…”

“…The phosphorylation process may occur in the time scale of hours, and be modulated by cumulative phosphorylation of multiple sites, e.g., casein kinase I (CKI) in the circadian regulation (Isojima et al, 2009;Shinohara et al, 2017). We note that the genes involved both in phosphorylation and sleep regulation are attractive candidates for the future studies on the homeostatic regulation of sleep (Ode et al, 2017;Tatsuki et al, 2017;Shi and Ueda, 2018).…”