A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of D-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter D-serine, by its precursor L-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards L-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.

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Publication Details

Journal
Nature Communications
Published
2024-08-09
DOI
https://doi.org/10.1038/s41467-024-51008-2
Citations
45
Primary Topic
Amino Acid Enzymes and Metabolism
Type
article
Field-Weighted Citation Impact
13.27

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article

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice

L. Felipe Barros, Gilles Bonvento, Guillaume Ferreira, Unai B. Fundazuri et al.
45 citations
Nature Communications
Amino Acid Enzymes and Metabolism
13.27
article

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice

L. Felipe Barros, Gilles Bonvento, Guillaume Ferreira, Unai B. Fundazuri, Gianluca Lavanco, Yusuke Nasu, Román Serrat, Luc Pellerin, Doriane Gisquet, Francisca Julio‐Kalajzić, Sarah Mountadem, Giovanni Marsicano, Filippo Drago, Juan P. Bolaños, Astrid Cannich, Ignacio Fernández‐Moncada, Anne‐Karine Bouzier‐Sore, Robert E. Campbell, Stéphane H. R. Oliet, Pauline Hachaguer, Aude Panatier, Tommaso Dalla Tor, Luigi Bellocchio, Carla Cannizzaro, Nasrin Bollmohr, Bérénice Fortunato-Marsol
article en
45 citations

Abstract

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of D-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter D-serine, by its precursor L-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards L-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.

Nature CommunicationsVol. 15(1)
Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Universidad de Salamanca (ES), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), San Sebastián University (CL), Université de Poitiers (FR), University of Catania (IT), Japan Science and Technology Agency (JP), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Centre de Résonance Magnétique des Systèmes Biologiques (FR), Department of Health (ES), Neurocentre Magendie (FR), CEA Paris-Saclay (FR), Instituto de Investigación Biomédica de Salamanca (ES), NutriNeuro (FR), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES), Instituto de Biología Funcional y Genómica (ES), Institut Polytechnique de Bordeaux (FR), Université Laval (CA), The University of Tokyo (JP), Centro de Estudios Científicos (CL), University of Palermo (IT)
European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Centre National de la Recherche Scientifique, Université de Bordeaux, FONDATION ALZHEIMER, Agencia Nacional de Investigación y Desarrollo, Japan Society for the Promotion of Science, Japan Science and Technology Agency, Agencia Estatal de Investigación
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Amino Acid Enzymes and Metabolism
13.27
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