title: Channel-mediated lactate release by K⁺-stimulated astrocytes.
abstract: 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.
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Tamara
authors.identifier: http://orcid.org/0000-0001-9094-9073
authors.initials: T
authors.lastname: Sotelo-Hitschfeld
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile.
authors.forename: María I
authors.initials: MI
authors.lastname: Niemeyer
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland, Neuroscience Center Zürich, University and ETH Zürich, 8092 Zürich, Switzerland.
authors.forename: Philipp
authors.identifier: http://orcid.org/0000-0001-7996-7684
authors.initials: P
authors.lastname: Mächler
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile.
authors.forename: Iván
authors.initials: I
authors.lastname: Ruminot
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Lerchundi
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland, Neuroscience Center Zürich, University and ETH Zürich, 8092 Zürich, Switzerland.
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wyss
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland, Neuroscience Center Zürich, University and ETH Zürich, 8092 Zürich, Switzerland.
authors.forename: Jillian
authors.initials: J
authors.lastname: Stobart
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fernández-Moncada
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile.
authors.forename: Rocío
authors.initials: R
authors.lastname: Valdebenito
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Garrido-Gerter
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Yasna
authors.initials: Y
authors.lastname: Contreras-Baeza
authors.affiliation: Brain Mind Institute, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Brain Mind Institute, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.affiliation: Brain Mind Institute, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lengacher
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: San Martín
authors.affiliation: Commissariat à l'Energie Atomique, Institut d'Imagerie Biomédicale, Molecular Imaging Research Center and Centre National de la Recherche Scientifique, Université Paris-Sud, Université Paris-Saclay, UMR 9199, F-92265 Fontenay-aux-Roses, France, and.
authors.forename: Juliette
authors.initials: J
authors.lastname: Le Douce
authors.affiliation: Commissariat à l'Energie Atomique, Institut d'Imagerie Biomédicale, Molecular Imaging Research Center and Centre National de la Recherche Scientifique, Université Paris-Sud, Université Paris-Saclay, UMR 9199, F-92265 Fontenay-aux-Roses, France, and.
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
authors.affiliation: Brain Mind Institute, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland, Division of Biological and Environmental Sciences and Engineering, Kaust, Saudi Arabia.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Magistretti
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile.
authors.forename: Francisco V
authors.initials: FV
authors.lastname: Sepúlveda
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland, Neuroscience Center Zürich, University and ETH Zürich, 8092 Zürich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Weber
authors.affiliation: Centro de Estudios Científicos, Valdivia 5110466, Chile, fbarros@cecs.cl.
authors.forename: L Felipe
authors.initials: LF
authors.lastname: Barros
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D001464:Barium / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007477:Ions / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000166:cytology / Q000502:physiology; D014162:Transfection
chemical_list: D005452:Fluoresceins; D007473:Ion Channels; D007477:Ions; D002104:Cadmium; D001464:Barium; D019344:Lactic Acid; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; D019289:Pyruvic Acid; D006003:Glycogen; D011188:Potassium
keywords: fluorescence microscopy; genetically encoded nanosensor; gliotransmission; membrane depolarization