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Role of Glia in the Regulation of Sleep in Health and Disease

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Sleep is a naturally occurring physiological state that is required to sustain physical and mental health. Traditionally viewed as strictly regulated by top‐down control mechanisms, sleep is now known to also originate locally. Glial cells are emerging as important contributors to the regulation of sleep‐wake cycles, locally and among dedicated neural circuits. A few pioneering studies revealed that astrocytes and microglia may influence sleep pressure, duration as well as intensity, but the precise involvement of these two glial cells in the regulation of sleep remains to be fully addressed, across contexts of health and disease. In this overview article, we will first summarize the literature pertaining to the role of astrocytes and microglia in the regulation of sleep under normal physiological conditions. Afterward, we will discuss the beneficial and deleterious consequences of glia‐mediated neuroinflammation, whether it is acute, or chronic and associated with brain diseases, on the regulation of sleep. Sleep disturbances are a main comorbidity in neurodegenerative diseases, and in several brain diseases that include pain, epilepsy, and cancer. Identifying the relationships between glia‐mediated neuroinflammation, sleep‐wake rhythm disruption and brain diseases may have important implications for the treatment of several disorders. © 2020 American Physiological Society. Compr Physiol 10:687‐712, 2020.

Figure 1. Figure 1. Schematic representation of the lactate/glutamate shuttle and glycogen metabolism, as well as pH and K+ buffering functions of astrocytes (i) pH buffering (orange pathway). Abundant carbonic anhydrase (CA) in astrocytes converts CO2 into H+ and HCO3. Two HCO3 are transported into the extracellular space along with one Na+ via the Na+‐HCO3 co‐transporter (NBC), thereby increasing the extracellular buffering power. Protons left in the glial compartment might drive the transport of lactate (Lac) outside of astrocytes and into neurons through monocarboxylate transporters (MCTs). Excess H+ in neurons is extruded via sodium‐hydrogen exchange (NHE). (ii) astrocyte‐neuron lactate shuttle (ANLS) (green pathway). Glutamate (Glu) uptake by astrocytes is accompanied by Na+ entry, which is extruded by the action of the Na+/K+ ATPase. This triggers glycolysis in astrocytes and glucose uptake from the circulation through GLUT1. The lactate produced is shuttled to neurons through MCTs, where it can be used as an energy substrate after its conversion to pyruvate (Pyr). Neurons can also take up glucose via the neuronal GLUT3. (iii) Glycogen metabolism (purple pathway). Astrocytes store glucose under the form of glycogen. Glycogen synthesis is controlled by glycogen synthase and by the noncatalytic subunit of the protein phosphatase 1 (PTG). The degradation is controlled by the glycogen phosphorylase (GPhos). (iv) Glu‐glutamine cycle (red pathway). Glu released into the synaptic cleft activates ionotropic glutamatergic receptors (GluR), producing a postsynaptic depolarization. Astrocytic excitatory amino acid transporters (EAATs) are responsible for the uptake of a large fraction of Glu at the synapse. Glu is converted into glutamine (Gln) by GS and shuttled back to neurons for glutamate resynthesis. (v) K+ buffering (blue pathway). Astrocytes buffer excess K+ released into the extracellular space as a result of neuronal activity [e.g., through inwardly rectifying K+ channels (Kir)]. K+ ions travel through the astrocytic network via gap junctions (GJ) down their concentration gradient and are released in sites of lower concentration. From Ref. 269.

Figure 1. Schematic representation of the lactate/glutamate shuttle and glycogen metabolism, as well as pH and K+ buffering functions of astrocytes (i) pH buffering (orange pathway). Abundant carbonic anhydrase (CA) in astrocytes converts CO2 into H+ and HCO3. Two HCO3 are transported into the extracellular space along with one Na+ via the Na+‐HCO3 co‐transporter (NBC), thereby increasing the extracellular buffering power. Protons left in the glial compartment might drive the transport of lactate (Lac) outside of astrocytes and into neurons through monocarboxylate transporters (MCTs). Excess H+ in neurons is extruded via sodium‐hydrogen exchange (NHE). (ii) astrocyte‐neuron lactate shuttle (ANLS) (green pathway). Glutamate (Glu) uptake by astrocytes is accompanied by Na+ entry, which is extruded by the action of the Na+/K+ ATPase. This triggers glycolysis in astrocytes and glucose uptake from the circulation through GLUT1. The lactate produced is shuttled to neurons through MCTs, where it can be used as an energy substrate after its conversion to pyruvate (Pyr). Neurons can also take up glucose via the neuronal GLUT3. (iii) Glycogen metabolism (purple pathway). Astrocytes store glucose under the form of glycogen. Glycogen synthesis is controlled by glycogen synthase and by the noncatalytic subunit of the protein phosphatase 1 (PTG). The degradation is controlled by the glycogen phosphorylase (GPhos). (iv) Glu‐glutamine cycle (red pathway). Glu released into the synaptic cleft activates ionotropic glutamatergic receptors (GluR), producing a postsynaptic depolarization. Astrocytic excitatory amino acid transporters (EAATs) are responsible for the uptake of a large fraction of Glu at the synapse. Glu is converted into glutamine (Gln) by GS and shuttled back to neurons for glutamate resynthesis. (v) K+ buffering (blue pathway). Astrocytes buffer excess K+ released into the extracellular space as a result of neuronal activity [e.g., through inwardly rectifying K+ channels (Kir)]. K+ ions travel through the astrocytic network via gap junctions (GJ) down their concentration gradient and are released in sites of lower concentration. From Ref. 269.
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Teaching Material

Stefano Garofalo, Katherine Picard, Cristina Limatola, Agnès Nadjar, Olivier Pascual, and Marie-Ève Tremblay. Role of Glia in the Regulation of Sleep in Health and Disease. Compr Physiol 10 : 2020, 687-712.

Didactic Synopsis

Major Teaching Points:

1. Sleep is a physiological state that involves the activity of glial cells.

2. The two main types of glial cells, astrocytes and microglia, play different roles in the regulation of sleep across health and disease.

3. Astrocytes and microglia both release cytokines that regulate sleep.

4. Astrocytes determine the urge to sleep by regulating extracellular adenosine levels and clearing toxic substances through the glymphatic system.

5. Less is known about the role of microglia during normal physiological conditions.

6. The physiological function of astrocytes and microglia is influenced by neuroinflammation, which modulates sleep.

7. Acute neuroinflammation promotes behaviors such as increased sleep that help to restore the challenged homeostasis.

8. Chronic neuroinflammation can lead to neurodegenerative diseases and other brain diseases, such as pain, epilepsy and cancer, in which sleep disorders are a main comorbidity.


9. Studying the involvement of glial cells in sleep disorders might identify new treatments.

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How to Cite

Stefano Garofalo, Katherine Picard, Cristina Limatola, Agnès Nadjar, Olivier Pascual, Marie‐Ève Tremblay. Role of Glia in the Regulation of Sleep in Health and Disease. Compr Physiol 2020, 10: 687-712. doi: 10.1002/cphy.c190022