An Epigenetic Model of Insomnia?

Abstract

Copyright: © 2013 Palagini L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Sleep is a complex physiological process and remain one of the great mysteries of science. Hypotheses for sleep include somatic, metabolic, cellular theories, as well as brain-specific functions such as synaptic plasticity, or synaptic downscaling. Over the past 10 years, genetics provides a new way to address the regulation and function of sleep. Major findings include the identification of loci that make quantitative contributions to sleep characteristics and variability. From Drosophila, zebrafish, and worms to mammalian model organisms, some genes implicated in sleep homeostatic regulation have beeen identified [1]. Circadian genes (Clock, PER1, 2, 3 Bmal1, Timeless), neurotransmitters (serotonin, dopamine, norepinephrine, histamine, acetylcholine, orexin/hypocretin (Orexin/Hcrtrt2), adenosine, GABA receptor), cytokines/immune or stress response genes (NfkB1, NfkB, TNF-α, BiP, IL-1b, IL-6, IL-10), synaptic transmission genes (Homer, c-Fos, Gria3), ion channels (K+ channels, Ca++ channels) and signal metabolic/cellular growth genes (Ghrelin Rho, Leptin EGF, Dwarf, GHRH) have been identified in mammalian. Moreover genetic determinants underlying variability in sleep phenotypes have begun to be revealed and reasearch of the past 10 years focussed on understanding factors contributing to sleep disturbances [2]. Well-documented familial and twin sleep disorder studies suggest an important influence of genetic factors. However only few sleep disorders have an established genetic basis including rare diseases that may result from a single gene mutation: fatal familial insomnia (mutation of prion protein gene PRNP), familial advanced sleep-phase syndrome (mutations in hPER2), delayed sleep phase syndrome (polymorphism in Per3) and narcolepsy with cataplexy (orexin/hypocretin genes) [1,2]. Indeed, most sleep disorders are complex in terms of their genetic susceptibility together with the variable expressivity of the phenotype and contribution of genes. Moreover environment and epigenetic gene-environment interactions have been recently hypothesized to control sleep and its disorders. In Drosophila, several histone modifications have been identified to contribute to chromatin remodeling and thereby to the epigenetic control of circadian gene expression [3]. Recently sleep regulation have been linked to activity-dependent epigenetic brain plasticity [4]. An alteration in both the histone Elp3, essential for the epigenetic control of neurogenesis [5] and the histone Tip60 which epigenetically regulates genes enriched for neuronal functions resulted involved in the sleep-wake regulation encompassing neural network in Drosophila [6]. This latter has been hypothesized to provide insight into epigenetic based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer’s disease [6].