Glucose metabolism links astroglial mitochondria to cannabinoid effects
Daniel Jimenez-Blasco
(1, 2, 3)
,
Arnau Busquets-Garcia
(4, 5, 6)
,
Etienne Hebert-Chatelain
(7)
,
Roman Serrat
(4)
,
Carlos Vicente-Gutierrez
(1, 2, 3)
,
Christina Ioannidou
(4)
,
Paula Gómez-Sotres
(4)
,
Irene Lopez-Fabuel
(1, 2, 3)
,
Monica Resch-Beusher
(1, 2, 3)
,
Eva Resel
(8, 9, 10)
,
Dorian Arnouil
(4)
,
Dave Saraswat
(4)
,
Marjorie Varilh
(4)
,
Astrid Cannich
(4)
,
Francisca Julio-Kalajzic
(4)
,
Itziar Bonilla-del Río
(11, 12)
,
Angeles Almeida
(1, 3)
,
Nagore Puente
(11, 12)
,
Svein Achicallende
(11, 12)
,
Maria-Luz Lopez-Rodriguez
(9)
,
Charlotte Jollé
(13)
,
Nicole Déglon
(13)
,
Luc Pellerin
(14, 15, 16)
,
Charlène Josephine
(17)
,
Gilles Bonvento
(18)
,
Aude Panatier
(4)
,
Beat Lutz
(19, 20)
,
Pier-Vincenzo Piazza
(4)
,
Manuel Guzmán
(8, 9, 10)
,
Luigi Bellocchio
(4)
,
Anne-Karine Bouzier-Sore
(16)
,
Pedro Grandes
(11, 12, 21)
,
Juan Bolaños
(1, 2, 3)
,
Giovanni Marsicano
(4)
1
Universidad de Salamanca [España] = University of Salamanca [Spain]
2 ISC - Instituto de Salud Carlos III [Madrid]
3 University Hospital of Salamanca
4 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
5 UB - Université de Bordeaux
6 IMIM-Hospital del Mar
7 Université de Moncton
8 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
9 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
10 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
11 UPV / EHU - University of the Basque Country = Euskal Herriko Unibertsitatea
12 Achucarro Basque Center for Neuroscience
13 UNIL - Université de Lausanne = University of Lausanne
14 IRTOMIT [Poitiers] - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques [U 1082]
15 Department of Physiology [Lausanne, Switzerland]
16 CRMSB - Centre de résonance magnétique des systèmes biologiques
17 MIRCEN - Molecular Imaging Research Center [Fontenay-aux-Roses]
18 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
19 University Medical Center [Mainz]
20 LIR Mainz - Leibniz Institute for Resilience Research [Mainz, Allemagne]
21 UVIC - University of Victoria [Canada]
2 ISC - Instituto de Salud Carlos III [Madrid]
3 University Hospital of Salamanca
4 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
5 UB - Université de Bordeaux
6 IMIM-Hospital del Mar
7 Université de Moncton
8 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
9 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
10 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
11 UPV / EHU - University of the Basque Country = Euskal Herriko Unibertsitatea
12 Achucarro Basque Center for Neuroscience
13 UNIL - Université de Lausanne = University of Lausanne
14 IRTOMIT [Poitiers] - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques [U 1082]
15 Department of Physiology [Lausanne, Switzerland]
16 CRMSB - Centre de résonance magnétique des systèmes biologiques
17 MIRCEN - Molecular Imaging Research Center [Fontenay-aux-Roses]
18 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
19 University Medical Center [Mainz]
20 LIR Mainz - Leibniz Institute for Resilience Research [Mainz, Allemagne]
21 UVIC - University of Victoria [Canada]
Daniel Jimenez-Blasco
- Fonction : Auteur
- PersonId : 803877
- ORCID : 0000-0002-1384-1832
Arnau Busquets-Garcia
- Fonction : Auteur
- PersonId : 793302
- ORCID : 0000-0002-7100-8873
Carlos Vicente-Gutierrez
- Fonction : Auteur
- PersonId : 803878
- ORCID : 0000-0002-6481-595X
Christina Ioannidou
- Fonction : Auteur
- PersonId : 800867
- ORCID : 0000-0003-2726-0403
- IdRef : 260425230
Irene Lopez-Fabuel
- Fonction : Auteur
- PersonId : 803879
- ORCID : 0000-0002-3049-748X
Svein Achicallende
- Fonction : Auteur
- PersonId : 800685
- ORCID : 0000-0002-9245-9761
Nicole Déglon
- Fonction : Auteur
- PersonId : 758857
- ORCID : 0000-0003-4475-9476
- IdRef : 143399365
Luc Pellerin
- Fonction : Auteur
- PersonId : 1397093
- ORCID : 0000-0002-1016-1970
- IdRef : 197013147
Gilles Bonvento
- Fonction : Auteur
- PersonId : 175993
- IdHAL : gilles-bonvento
- ORCID : 0000-0002-2886-4228
- IdRef : 135322839
Aude Panatier
- Fonction : Auteur
- PersonId : 1085331
- IdHAL : aude-panatier
- ORCID : 0000-0002-6107-4463
- IdRef : 114383049
Anne-Karine Bouzier-Sore
- Fonction : Auteur
- PersonId : 758351
- ORCID : 0000-0002-3470-0940
- IdRef : 197013473
Juan Bolaños
- Fonction : Auteur
- PersonId : 798007
- ORCID : 0000-0002-3949-6862
Giovanni Marsicano
- Fonction : Auteur
- PersonId : 923097
- ORCID : 0000-0003-3804-1951
- IdRef : 150614934
Résumé
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.