Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling

Abstract

Major depressive disorder is a debilitating condition with a lifetime risk of ten percent. Most treatments take several weeks to achieve clinical efficacy, limiting the ability to bring instant relief needed in psychiatric emergencies. One intervention that rapidly alleviates depressive symptoms is sleep deprivation; however, its mechanism of action is unknown. Astrocytes regulate responses to sleep deprivation, raising the possibility that glial signaling mediates antidepressive-like actions of sleep deprivation. Here, we found that astrocytic signaling to adenosine (A1) receptors was required for the robust reduction of depressive-like behaviors following 12 hours of sleep deprivation. As sleep deprivation activates synaptic A1 receptors, we mimicked the effect of sleep deprivation on depression phenotypes by administration of the A1 agonist CCPA. These results provide the first mechanistic insight into how sleep deprivation impacts mood, and provide a novel pathway for rapid antidepressant development by modulation of glial signaling in the brain.

Recovery sleep after extended wakefulness restores elevated A 1 adenosine receptor availability in the human brain

“…Interestingly, S-adenosylmethionine, a precursor of adenosine, is a widely used over-the-counter medication of major depression (50). More directly, it was recently shown in a readout model of antidepressive effects (forced swim test in mice) that astrocytic adenosine signaling to A 1 AR during sleep deprivation is necessary to reduce depressive-like behaviors (21). Up-regulating A 1 AR in a transgenic mouse model of conditionally enhanced forebrain A 1 AR expression promoted resilience against depression-resembling reactions in various behavioral tests (51).…”

“…In contrast, healthy individuals show negative effects concerning mood, alertness, and cognition. Adenosine-related interactions are also crucial in astrocyte-neuron communication, which underlies both cortical sleep (20) and also antidepressive effects of sleep deprivation (21). Apart from extracellular adenosine itself, evidence exists for the mediating subtype of adenosine receptors to regulate sleep-wake rhythmicity.…”

Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

“…A study showed that the anticonvulsant effect of tianeptine, an atypical antidepressant, is mediated by the activation of adenosine A 1 receptors [57]. In addition, the activation of adenosine A 1 receptors is required for the antidepressant effect of sleep deprivation [58]. In preclinical models, CCPA, a selective adenosine A 1 receptor agonist, reduced immobility time in the forced swimming test, an effect that is sustained for 36 h following its administration [58].…”

“…In addition, the activation of adenosine A 1 receptors is required for the antidepressant effect of sleep deprivation [58]. In preclinical models, CCPA, a selective adenosine A 1 receptor agonist, reduced immobility time in the forced swimming test, an effect that is sustained for 36 h following its administration [58]. Moreover, adenosine A 1 receptor agonist CHA induces antidepressant-like profile in rats [59].…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…More recently, it was found that the rapid antidepressantlike effect of sleep deprivation is mediated by astrocyte-derived adenosine as it is absent in A 1 receptor knockout and astrocytedeficient dnSNARE mice and can be mimicked by CCPA, an A 1 -selective agonist (Hines et al, 2013). Further, astrocyte-specific deletion of A 2A receptors mimics certain features of the schizophrenia endophenotype, such as decreased working memory and enhanced psychomotor response to the NMDA antagonist MK-801 (Matos et al, 2015).…”