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

Ignacio Fernández-Moncada (), Gianluca Lavanco, Unai B. Fundazuri, Nasrin Bollmohr, Sarah Mountadem, Tommaso Dalla Tor, Pauline Hachaguer, Francisca Julio-Kalajzic, Doriane Gisquet, Roman Serrat, Luigi Bellocchio, Astrid Cannich, Bérénice Fortunato-Marsol, Yusuke Nasu, Robert E. Campbell, Filippo Drago, Carla Cannizzaro, Guillaume Ferreira, Anne-Karine Bouzier-Sore, Luc Pellerin, Juan P. Bolaños, Gilles Bonvento, L. Felipe Barros, Stephane H. R. Oliet, Aude Panatier and Giovanni Marsicano ()
Additional contact information
Ignacio Fernández-Moncada: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Gianluca Lavanco: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Unai B. Fundazuri: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Nasrin Bollmohr: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Sarah Mountadem: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Tommaso Dalla Tor: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Pauline Hachaguer: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Francisca Julio-Kalajzic: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Doriane Gisquet: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Roman Serrat: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Luigi Bellocchio: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Astrid Cannich: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Bérénice Fortunato-Marsol: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Yusuke Nasu: The University of Tokyo
Robert E. Campbell: The University of Tokyo
Filippo Drago: University of Catania
Carla Cannizzaro: University of Palermo
Guillaume Ferreira: Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286
Anne-Karine Bouzier-Sore: Univ. Bordeaux, CNRS, Centre de Résonance Magnétique des Systèmes Biologiques, UMR 5536
Luc Pellerin: Université de Poitiers et CHU de Poitiers, INSERM, IRMETIST, U1313
Juan P. Bolaños: Universidad de Salamanca, CSIC
Gilles Bonvento: Universite Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodegeneratives
L. Felipe Barros: Centro de Estudios Cientificos
Stephane H. R. Oliet: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Aude Panatier: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215
Giovanni Marsicano: Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51008-2

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