A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice.
Nat Commun. 2024-08-09; 15(1):
DOI: 10.1038/s41467-024-51008-2
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Fernández-Moncada I(1), Lavanco G(#)(2)(3)(4), Fundazuri UB(#)(2), Bollmohr
N(#)(2), Mountadem S(#)(2), Dalla Tor T(#)(2)(3), Hachaguer P(2), Julio-Kalajzic
F(2), Gisquet D(2), Serrat R(2)(5), Bellocchio L(2), Cannich A(2),
Fortunato-Marsol B(2), Nasu Y(6)(7), Campbell RE(6)(8), Drago F(3), Cannizzaro
C(9), Ferreira G(5), Bouzier-Sore AK(10), Pellerin L(11), Bolaños
JP(12)(13)(14), Bonvento G(15), Barros LF(16)(17), Oliet SHR(2), Panatier A(2),
Marsicano G(18).
Author information:
(1)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux,
France. .
(2)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux,
France.
(3)Department of Biomedical and Biotechnological Sciences, Section of
Pharmacology, University of Catania, Catania, Italy.
(4)Department of Health Promotion, Mother and Child Care, Internal Medicine and
Medical Specialties, ”G. D’Alessandro”, University of Palermo, Palermo, Italy.
(5)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux,
France.
(6)Department of Chemistry, School of Science, The University of Tokyo,
Bunkyo-ku, Tokyo, Japan.
(7)PRESTO, Japan Science and Technology Agency, Chiyoda-ku, Tokyo, Japan.
(8)CERVO Brain Research Center and Department of Biochemistry, Microbiology, and
Bioinformatics, Université Laval, Québec City, QC, Canada.
(9)Department of Biomedicine, Neuroscience and Advanced Diagnostics, University
of Palermo, Palermo, Italy.
(10)Univ. Bordeaux, CNRS, Centre de Résonance Magnétique des Systèmes
Biologiques, UMR 5536, F-33000, Bordeaux, France.
(11)Université de Poitiers et CHU de Poitiers, INSERM, IRMETIST, U1313,
Poitiers, France.
(12)Institute of Functional Biology and Genomics (IBFG), Universidad de
Salamanca, CSIC, Salamanca, Spain.
(13)Institute of Biomedical Research of Salamanca (IBSAL), Hospital
Universitario de Salamanca, Salamanca, Spain.
(14)Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento
Saludable (CIBERFES), Madrid, Spain.
(15)Universite Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies
Neurodegeneratives, Fontenay-aux-Roses, France.
(16)Centro de Estudios Cientificos, Valdivia, Chile.
(17)Facultad de Medicina y Ciencia, Universidad San Sebastián, Valdivia, Chile.
(18)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux,
France. .
(#)Contributed equally
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.
© 2024. The Author(s).
Conflict of interest statement: The authors declare no competing interests.