A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans

Abstract

Slow, rhythmic oscillations (<5 Hz) in the sleep electroencephalogram may be a sign of synaptic plasticity occurring during sleep. The oscillations, referred to as slow-wave activity (SWA), reflect sleep need and sleep intensity. The amount of SWA is homeostatically regulated. It is enhanced after sleep loss and declines during sleep. Animal studies suggested that sleep need is genetically controlled, yet the physiological mechanisms remain unknown. Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep. In contrast, a distinct polymorphism of the adenosine A 2A receptor gene, which was associated with interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers, affects the electroencephalogram during sleep and wakefulness in a non-state-specific manner. Our findings indicate a direct role of adenosine in human sleep homeostasis. Moreover, our data suggest that genetic variability in the adenosinergic system contributes to the interindividual variability in brain electrical activity during sleep and wakefulness.electroencephalography ͉ G protein-coupled receptor ͉ synaptic transmission T he homeostatic regulation of rest and sleep is a common principle in invertebrates, fish, and mammals (1). Sleep homeostasis has been associated with local synaptic plasticity (2). Sleep homeostasis implies that increased sleep need associated with prolonged wakefulness results in compensatory changes in sleep duration and, particularly, in sleep intensity during subsequent sleep. It has long been observed in humans that the duration of deep, non-rapid-eye-movement (non-REM) sleep, i.e., slow-wave sleep, is homeostatically regulated (3, 4). Moreover, electroencephalogram (EEG) slow-wave activity (power within Ϸ0.5-5 Hz) during sleep and theta͞low-alpha activity (Ϸ5-9 Hz) during wakefulness are robust physiological markers of sleep need and sleep intensity (5-7). Although these regulatory characteristics are well established (8), the neurochemical and molecular mechanisms underlying sleep homeostasis are unknown.The neuromodulator adenosine was proposed to provide a neurochemical substrate contributing to sleep homeostasis. Converging lines of evidence, primarily from electrophysiological, microdialysis, and pharmacological animal studies, accumulated in past decades to support an important role of adenosine, as well as adenosine A 1 and A 2A receptors, in sleep and sleep regulation (see refs. 9 -12 for recent overviews). Moreover, quantitative trait loci analyses in mice revealed that a genomic region containing the genes of two adenosinemetabolizing enzymes, adenosine deaminase (ADA) and Sadenosyl-homocysteine hydrolase, modifies the rate at which sleep need accumulates during wakefulness (13). This mouse quantitative trait locus is homologue to a region on the human chromosome 20 that contains the gene that encodes ADA (14). More than 30 allelic variants o...

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