Channel-mediated lactate release by K+ stimulated astrocytes
Journal of Neuroscience. 2015-03-11; 35(10): 4168-4178
DOI: 10.1523/JNEUROSCI.5036-14.2015
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Excitatory synaptic transmission is accompanied by a local surge in interstitial
lactate that occurs despite adequate oxygen availability, a puzzling phenomenon
termed aerobic glycolysis. In addition to its role as an energy substrate, recent
studies have shown that lactate modulates neuronal excitability acting through
various targets, including NMDA receptors and G-protein-coupled receptors
specific for lactate, but little is known about the cellular and molecular
mechanisms responsible for the increase in interstitial lactate. Using a panel of
genetically encoded fluorescence nanosensors for energy metabolites, we show here
that mouse astrocytes in culture, in cortical slices, and in vivo maintain a
steady-state reservoir of lactate. The reservoir was released to the
extracellular space immediately after exposure of astrocytes to a physiological
rise in extracellular K(+) or cell depolarization. Cell-attached patch-clamp
analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel
activated by cell depolarization. The channel was modulated by lactate itself,
resulting in a positive feedback loop for lactate release. A rapid fall in
intracellular lactate levels was also observed in cortical astrocytes of
anesthetized mice in response to local field stimulation. The existence of an
astrocytic lactate reservoir and its quick mobilization via an ion channel in
response to a neuronal cue provides fresh support to lactate roles in neuronal
fueling and in gliotransmission.