A cannabinoid link between mitochondria and memory.
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1receptors. Genetic exclusion of CB1receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1receptors signal through intra-mitochondrial Gαiprotein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.|Department of Biology, Université de Moncton, Moncton, New-Brunswick E1A 3E9, Canada.
Etienne
E
Hebert-Chatelain
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Tifany
T
Desprez
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Román
R
Serrat
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.|Department of Biochemistry and Molecular Biology I, Complutense University, Madrid 28040, Spain.
Luigi
L
Bellocchio
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Edgar
E
Soria-Gomez
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Arnau
A
Busquets-Garcia
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Antonio Christian
AC
Pagano Zottola
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Anna
A
Delamarre
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Astrid
A
Cannich
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Peggy
P
Vincent
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Marjorie
M
Varilh
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Laurie M
LM
Robin
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Geoffrey
G
Terral
Department of Research and Development, IMG Pharma Biotech S.L., Derio 48160, Spain.|Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa 48940, Spain.
M Dolores
MD
García-Fernández
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.|Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95124, Italy.
Michelangelo
M
Colavita
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Wilfrid
W
Mazier
Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95124, Italy.
Filippo
F
Drago
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa 48940, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, Zamudio 48170, Spain.
Nagore
N
Puente
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa 48940, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, Zamudio 48170, Spain.
Leire
L
Reguero
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa 48940, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, Zamudio 48170, Spain.
Izaskun
I
Elezgarai
Université de Bordeaux, Centre Génomique Fonctionnelle, Plateforme Protéome, Bordeaux 33077, France.
Jean-William
JW
Dupuy
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Daniela
D
Cota
Department of Organic Chemistry, Complutense University, Madrid 28040, Spain.
Maria-Luz
ML
Lopez-Rodriguez
Department of Research and Development, IMG Pharma Biotech S.L., Derio 48160, Spain.
Gabriel
G
Barreda-Gómez
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Federico
F
Massa
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa 48940, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, Zamudio 48170, Spain.|Division of Medical Sciences, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada.
Pedro
P
Grandes
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Giovanni
G
Bénard
INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.|Université de Bordeaux, NeuroCentre Magendie, Bordeaux 33077, France.
Giovanni
G
Marsicano
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002186:Cannabinoids / Q000009:adverse effects* / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D009245:NADH Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; C000610360:Ndufs2 protein, mouse