Professor Dan Yang, an academician of the National Academy of Sciences and University of California, Berkeley, published a research paper titled "Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission" in the journal Nature Neuroscience. The study found that activation of inhibitory G protein (Gi protein) signaling in microglia, immune cells in the brain, promotes sleep, and that this effect is mediated, at least in part, through its intracellular Ca2+ signaling, resulting in a decrease in extracellular norepinephrine (NE) concentration.
Sleep plays a critical role in brain health and function by promoting multiple physiological processes, including homeostatic regulation of neuronal activity, synaptic strength, and clearance of metabolic waste products. Microglia are the primary immune cells in the brain and play a key role in brain homeostasis by regulating neuronal activity, pruning synapses, and clearing away cellular debris and harmful aggregates. Both sleep disorders and microglial dysfunction have been implicated in a variety of neurodegenerative diseases. However, the role of microglia in sleep regulation is only beginning to be investigated.
In the healthy brain, microglia are in a homeostatic state characterized by branched morphology and expression of specific genes that support homeostatic function. One of the homeostatic genes encodes P2Y12, an inhibitory G protein (Gi protein)-coupled ATP/ADP receptor that is highly expressed in microglia within the central nervous system (CNS). P2Y12 is critical for the function of microglia, particularly in their sensing and modulation of neuronal activity, promotion of experience-dependent plasticity, and protection against epilepsy and ischemic brain injury. The ligands of P2Y12, ATP and ADP, and their metabolite adenosine, play important roles in homeostatic sleep regulation.
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Therefore, the research team began to explore the role of microglial P2Y12-Gi signaling in regulating sleep.
In this study, the research team demonstrated through mouse experiments that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+ signaling, and inhibition of norepinephrine (Norepinephrine, NE) transmission. Chemogenetic activation of microglial Gi signaling strongly promotes sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors reduces sleep. Two-photon imaging in the cerebral cortex showed that P2Y12-Gi activation increased intramicroglial Ca2+ levels, and blockade of this Ca2+ increase largely abolished the Gi-induced increase in sleep.
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Microglial Ca2+ levels also increase during the natural wake-to-sleep transition, in part due to reduced norepinephrine levels. Furthermore, imaging using a biosensor for norepinephrine (NE) in the cortex showed that microglial P2Y12-Gi activation significantly reduced norepinephrine levels, in part due to increased adenosine concentrations. These findings suggest that microglia may regulate sleep through interactions with norepinephrine transport.
Figure 1. Suppression of NE transmission by microglia Gi signaling is partly mediated by elevated adenosine level. (Ma C, et al., 2024)
Sleep disruption is increasingly recognized as an important risk factor for Alzheimer's disease and other neurodegenerative diseases, and loss of microglial homeostatic function is associated with sleep-wake disruption and progression of these diseases. The findings suggest an explanation: sleep-promoted increases in microglial Ca2+ may allow for more efficient monitoring and clearance of harmful extracellular proteins involved in neurodegenerative diseases; in turn, microglia actively promote sleep to maintain brain homeostasis.
Reference
Ma C, et al. Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission. Nature Neuroscience, 2024: 1-10.