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bioRxiv · 10.1101/2024.02.23.581817

Kir6.2-KATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis

Constantino, N. J.·Carroll, C. M.·Williams, H. C.·Yuede, C. M.·Sheehan, P. W.·Snipes, J. A.·Musiek, E. S.·Johnson, L. A.·Macauley, S. L.
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Abstract

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal KATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. HighlightsO_LIGlycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. C_LIO_LIWith Kir6.2-KATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. C_LIO_LIKir6.2-KATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/581817v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@11640c6org.highwire.dtl.DTLVardef@1f6a88corg.highwire.dtl.DTLVardef@b38daborg.highwire.dtl.DTLVardef@1a061f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Constantino, N. J., Carroll, C. M., Williams, H. C., Yuede, C. M., Sheehan, P. W., Snipes, J. A., Musiek, E. S., Johnson, L. A., Macauley, S. L.. 2024-02-28. Kir6.2-KATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis. https://doi.org/10.1101/2024.02.23.581817

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