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; Giovanni Marsicano

doi:10.1038/s41467-024-51008-2

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 PellerinJuan P. Bolaños, Gilles Bonvento, L. Felipe Barros, Stephane H.R. Oliet, Aude Panatier, Giovanni Marsicano^*

^*Corresponding author for this work

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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.

Translated title of the contribution	Un cambio hacia la glicólisis inducido por lactato media procesos sinápticos y cognitivos en ratones machos
Original language	English
Article number	6842
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-51008-2
State	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Medicine

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Fernandez-Moncada NatCom Lactate s41467-024-51008-2Final published version, 1.91 MB

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Fernández-Moncada, I., Lavanco, G., Fundazuri, U. B., Bollmohr, N., Mountadem, S., Dalla Tor, T., Hachaguer, P., Julio-Kalajzic, F., Gisquet, D., Serrat, R., Bellocchio, L., Cannich, A., Fortunato-Marsol, B., Nasu, Y., Campbell, R. E., Drago, F., Cannizzaro, C., Ferreira, G., Bouzier-Sore, A. K., ... Marsicano, G. (2024). A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice. Nature Communications, 15(1), Article 6842. https://doi.org/10.1038/s41467-024-51008-2

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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.",

author = "Ignacio Fern{\'a}ndez-Moncada and Gianluca Lavanco and Fundazuri, {Unai B.} and Nasrin Bollmohr and Sarah Mountadem and {Dalla Tor}, Tommaso and Pauline Hachaguer and Francisca Julio-Kalajzic and Doriane Gisquet and Roman Serrat and Luigi Bellocchio and Astrid Cannich and B{\'e}r{\'e}nice Fortunato-Marsol and Yusuke Nasu and Campbell, {Robert E.} and Filippo Drago and Carla Cannizzaro and Guillaume Ferreira and Bouzier-Sore, {Anne Karine} and Luc Pellerin and Bola{\~n}os, {Juan P.} and Gilles Bonvento and Barros, {L. Felipe} and Oliet, {Stephane H.R.} and Aude Panatier and Giovanni Marsicano",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-51008-2",

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Fernández-Moncada, I, Lavanco, G, Fundazuri, UB, Bollmohr, N, Mountadem, S, Dalla Tor, T, Hachaguer, P, Julio-Kalajzic, F, Gisquet, D, Serrat, R, Bellocchio, L, Cannich, A, Fortunato-Marsol, B, Nasu, Y, Campbell, RE, Drago, F, Cannizzaro, C, Ferreira, G, Bouzier-Sore, AK, Pellerin, L, Bolaños, JP, Bonvento, G, Barros, LF, Oliet, SHR, Panatier, A & Marsicano, G 2024, 'A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice', Nature Communications, vol. 15, no. 1, 6842. https://doi.org/10.1038/s41467-024-51008-2

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T1 - A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice

AU - Fernández-Moncada, Ignacio

AU - Lavanco, Gianluca

AU - Fundazuri, Unai B.

AU - Bollmohr, Nasrin

AU - Mountadem, Sarah

AU - Dalla Tor, Tommaso

AU - Hachaguer, Pauline

AU - Julio-Kalajzic, Francisca

AU - Gisquet, Doriane

AU - Serrat, Roman

AU - Bellocchio, Luigi

AU - Cannich, Astrid

AU - Fortunato-Marsol, Bérénice

AU - Nasu, Yusuke

AU - Campbell, Robert E.

AU - Drago, Filippo

AU - Cannizzaro, Carla

AU - Ferreira, Guillaume

AU - Bouzier-Sore, Anne Karine

AU - Pellerin, Luc

AU - Bolaños, Juan P.

AU - Bonvento, Gilles

AU - Barros, L. Felipe

AU - Oliet, Stephane H.R.

AU - Panatier, Aude

AU - Marsicano, Giovanni

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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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DO - 10.1038/s41467-024-51008-2

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

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