Microglia Regulate Sleep via Calcium-Dependent Modulation of Norepinephrine Transmission

Ma, C.; Li, B.; Silverman, D.; Ding, X.; Li, A.; Xiao, C.; Huang, G.; Worden, K.; Muroy, S.; Chen, W.; Xu, Z.; Tso, C. F.; Huang, Y.; Zhang, Y.; Luo, Q.; Saijo, K.; Dan, Y.

doi:10.1101/2023.07.24.550176

bioRxiv · 10.1101/2023.07.24.550176

Microglia Regulate Sleep via Calcium-Dependent Modulation of Norepinephrine Transmission

Ma, C.·Li, B.·Silverman, D.·Ding, X.·Li, A.·Xiao, C.·Huang, G.·Worden, K.·Muroy, S.·Chen, W.·Xu, Z.·Tso, C. F.·Huang, Y.·Zhang, Y.·Luo, Q.·Saijo, K.·Dan, Y.

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Abstract

Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia - the resident immune cells in the brain - remains poorly understood. Here we show that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+ signaling, and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging showed that P2Y12/Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+ elevation largely abolished the Gi-induced sleep increase. Microglia Ca2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine. Furthermore, imaging of norepinephrine activity with its biosensor showed that microglia P2Y12/Gi activation significantly reduced norepinephrine, partly by increasing the adenosine concentration. Thus, microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.

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Ma, C., Li, B., Silverman, D., Ding, X., Li, A., Xiao, C., Huang, G., Worden, K., Muroy, S., Chen, W., Xu, Z., Tso, C. F., Huang, Y., Zhang, Y., Luo, Q., Saijo, K., Dan, Y.. 2023-07-26. Microglia Regulate Sleep via Calcium-Dependent Modulation of Norepinephrine Transmission. https://doi.org/10.1101/2023.07.24.550176

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