Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss

Abstract

Astrocytes modulate neuronal activity by releasing chemical transmitters via a process termed gliotransmission. The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation. Inhibiting gliotransmission attenuated the accumulation of sleep pressure, assessed by measuring the slow wave activity of the EEG during NREM sleep and prevented cognitive deficits associated with sleep loss. Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wildtype mice mimicked the transgenic phenotype we conclude that astrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors.

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…Recent evidence strongly suggests a role for extracellular adenosine as an endogenous somnogen. 53,57,[60][61][62][63][64] ATP can act as a somnogen not only through its conversion to adenosine but also through the binding of extracellular ATP to P2-type transmembrane receptors, a step that leads to the release, largely from microglial cells (brain phagocytes), of cytokines that include interleukin-1b (IL1b) and tumor necrosis factor (TNF)-a. 56,65,66 As described below, these and other inflammatory cytokines can act as somnogens, indicating a major but incompletely understood connection between the immune system and sleep.…”

Integrated Brain Circuits: Neuron-Astrocyte Interaction in Sleep-Related Rhythmogenesis

“…Based on the early studies of gliotransmission, the concept of the tripartite synapse was proposed[94], highlighting the role of the astrocyte as a third active element in information processing at the synapse[95,96,97,98,99]. Although many aspects of this astrocytes-to-neuron communication are still to be elucidated[89,100] (for reviews, see [101,102,103]), the introduction of molecular genetic tools[83] is shedding light on the neuromodulatory roles of astrocytes on brain function at the level of synapses[83], circuits[104], and behavior[105]. …”

“…By studying the natural sleep behavior of dnSNARE mice with chronic EEG recordings, we observed that these animals show impaired accumulation of slow wave activity (SWA) as a function of prior wakefulness[105]. This deficit is present both under baseline conditions (while animals are undisturbed in their cages) and following sleep deprivation by gentle handling.…”

“…In our studies, the SWA phenotype observed in dnSNARE animals is mimicked by pharmacological blockade of A1 receptors in wild-type mice, suggesting that astrocytes represent a source of extracellular adenosine that activates neuronal A1 receptors to control sleep pressure accumulation. Moreover, both dnSNARE animals and their pharmacological phenocopies show resistance of the cognitive effects of short-term sleep deprivation[105]. The opposing roles of purinergic gliotransmission on cognitive function in the short vs. the long term point to intriguing ways in which the brain deals with chronic stressors and how this results in adaptive physiological changes to enhance behavioral performance.…”

Windows to cell function and dysfunction: Signatures written in the boundary layers

“…The chemical dynamics within this space are hypothesized to play key roles in cancer, spreading depression, epilepsy and sleep disorders. (3)(4)(5)(6) The purpose of this essay is to consider what we can learn from this space and the methods for following the dynamics of chemical movement within the diffusive boundary layers that comprise an integral part of a cell. We will start by noting the physical and chemical features involved.…”