NH4(+) triggers the release of astrocytic lactate via mitochondrial pyruvate shunting
Neural activity is accompanied by a transient mismatch between localglucose and oxygen metabolism, a phenomenon of physiological andpathophysiological importance termed aerobic glycolysis. Previousstudies have proposed glutamate and K+as the neuronal signals thattrigger aerobic glycolysis in astrocytes. Here we used a panel of ge-netically encoded FRET sensors in vitro and in vivo to investigate theparticipation of NH+4, a by-product of catabolism that is also releasedby active neurons. Astrocytes in mixed cortical cultures responded tophysiological levels of NH+4with an acute rise in cytosolic lactatefollowed by lactate release into theextracellular space, as detectedby a lactate-sniffer. An acute increase in astrocytic lactate was alsoobserved in acute hippocampal slices exposed to NH+4andinthesomatosensory cortex of anesthetized mice in response to i.v. NH+4.Unexpectedly, NH+4had no effect on astrocytic glucose consumption.Parallel measurements showed simultaneous cytosolic pyruvate accu-mulation and NADH depletion, suggesting the involvement of mito-chondria. An inhibitor-stop technique confirmed a strong inhibition ofmitochondrial pyruvate uptake that can be explained by mitochon-drial matrix acidification. These results show that physiological NH+4diverts the flux of pyruvate from mitochondria to lactate productionand release. Considering that NH+4is produced stoichiometrically withglutamate during excitatory neurotransmission, we propose thatNH+4behaves as an intercellular signal and that pyruvate shuntingcontributes to aerobic lactate production by astrocytes.
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