Glucose metabolism links astroglial mitochondria to cannabinoid effects

Daniel Jimenez-Blasco, Arnau Busquets-Garcia, Etienne Hebert-Chatelain, Roman Serrat, Carlos Vicente-Gutierrez, Christina Ioannidou, Paula Gómez-Sotres, Irene Lopez-Fabuel, Monica Resch-Beusher, Eva Resel, Dorian Arnouil, Dave Saraswat, Marjorie Varilh, Astrid Cannich, Francisca Julio-Kalajzic, Itziar Bonilla-Del Río, Angeles Almeida, Nagore Puente, Svein Achicallende, Maria-Luz Lopez-Rodriguez, Charlotte Jollé, Nicole Déglon, Luc Pellerin, Charlène Josephine, Gilles Bonvento, Aude Panatier, Beat Lutz, Pier-Vincenzo Piazza, Manuel Guzmán, Luigi Bellocchio, Anne-Karine Bouzier-Sore, Pedro Grandes, Juan P. Bolaños () and Giovanni Marsicano ()
Additional contact information
Daniel Jimenez-Blasco: University of Salamanca, CSIC
Arnau Busquets-Garcia: INSERM, U1215 NeuroCentre Magendie
Etienne Hebert-Chatelain: Université de Moncton
Roman Serrat: INSERM, U1215 NeuroCentre Magendie
Carlos Vicente-Gutierrez: University of Salamanca, CSIC
Christina Ioannidou: INSERM, U1215 NeuroCentre Magendie
Paula Gómez-Sotres: INSERM, U1215 NeuroCentre Magendie
Irene Lopez-Fabuel: University of Salamanca, CSIC
Monica Resch-Beusher: University of Salamanca, CSIC
Eva Resel: Complutense University
Dorian Arnouil: INSERM, U1215 NeuroCentre Magendie
Dave Saraswat: INSERM, U1215 NeuroCentre Magendie
Marjorie Varilh: INSERM, U1215 NeuroCentre Magendie
Astrid Cannich: INSERM, U1215 NeuroCentre Magendie
Francisca Julio-Kalajzic: INSERM, U1215 NeuroCentre Magendie
Itziar Bonilla-Del Río: University of the Basque Country (UPV/EHU)
Angeles Almeida: University of Salamanca, CSIC
Nagore Puente: University of the Basque Country (UPV/EHU)
Svein Achicallende: University of the Basque Country (UPV/EHU)
Maria-Luz Lopez-Rodriguez: Complutense University
Charlotte Jollé: University of Lausanne
Nicole Déglon: University of Lausanne
Luc Pellerin: University of Lausanne
Charlène Josephine: Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives
Gilles Bonvento: Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives
Aude Panatier: INSERM, U1215 NeuroCentre Magendie
Beat Lutz: University Medical Center
Pier-Vincenzo Piazza: INSERM, U1215 NeuroCentre Magendie
Manuel Guzmán: Complutense University
Luigi Bellocchio: INSERM, U1215 NeuroCentre Magendie
Anne-Karine Bouzier-Sore: CNRS-University of Bordeaux
Pedro Grandes: University of the Basque Country (UPV/EHU)
Juan P. Bolaños: University of Salamanca, CSIC
Giovanni Marsicano: INSERM, U1215 NeuroCentre Magendie

Nature, 2020, vol. 583, issue 7817, 603-608

Abstract: Abstract Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses1–5. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors5–7. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB1) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB1 receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.

Date: 2020
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DOI: 10.1038/s41586-020-2470-y

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