Regulation of sleep homeostasis mediator (adenosine) in the mouse — mostly by glutamatergic neurons

At first glance, this topic might not seem to be related to the GEITP theme of gene-environment interactions. However, the “environmental signal” (in this case, an endogenous compound from cells other than the target neurons) is a “somnogenic factor” and the gene response in these neurons is to induce sleep in the animal. Homeostatic regulation is a fundamental phenomenon of the sleep-wake cycle, whereby sleep-promoting “somnogenic factors” accumulate in the brain during our waking hours, ultimately inducing sleep. Several extracellular or cytoplasmic factors and associated genetic pathways that contribute to this phenomenon have been identified. Different patterns of neural activity in the brain control the sleep-wake cycle — but how this neural activity contributes to sleep homeostasis — remains largely unknown.

Among various processes implicated in controlling sleep homeostasis, release of adenosine in the basal forebrain is a prominent physiological mediator of sleep homeostasis. Authors [see attached article] used a genetically encoded adenosine sensor to examine in detail the mechanisms underlying increases in adenosine concentration in the basal forebrain. To record the dynamics of extracellular adenosine levels in the basal forebrain during the sleep-wake cycle with high temporal resolution and high specificity and sensitivity, authors designed, and optimized, a G protein–coupled receptor (GPCR)–activation–based (GRAB) sensor for adenosine (GRABAdo) — in which the amount of extracellular adenosine is indicated by the intensity of fluorescence produced by green fluorescent protein (GFP).

Authors [see attached article] then used human embryonic kidney 293T (HEK293T) cultured cells — to show unequivocal membrane-trafficking of adenosine when a saturated concentration of adenosine (100 mM) was administered to the cells in culture; in contrast, a non–ligand-binding mutant form of the sensor showed no detectable response. Using this newly developed genetically-designed adenosine sensor, authors found an activity-dependent rapid increase in extracellular adenosine levels — most specifically in mouse basal forebrain.

Although activity of both cholinergic and glutamatergic neurons in the basal forebrain correlated with changes in the adenosine concentrations, activation of neurons at physiological firing frequencies showed that glutamatergic neurons contributed much greater to the increased adenosine. Mice — having selective ablation of basal forebrain glutamatergic neurons — exhibited a much diminished adenosine-induced response, as well as impaired sleep homeostasis regulation. Therefore, these data show that cell type–specific neural activity in the basal forebrain is most important in dynamically controling sleep homeostasis. 😊


Science 4 Sept 2020; 369: 1208 eabb0556

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