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Nature. 2016 Nov 24;539(7630):555-559. doi: 10.1038/nature20127. Epub 2016 Nov 9.

A cannabinoid link between mitochondria and memory.

Author information

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.
Department of Biochemistry and Molecular Biology I, Complutense University, Madrid 28040, Spain.
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.
Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95124, Italy.
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.
Université de Bordeaux, Centre Génomique Fonctionnelle, Plateforme Protéome, Bordeaux 33077, France.
Department of Organic Chemistry, Complutense University, Madrid 28040, Spain.
Division of Medical Sciences, University of Victoria, Victoria, British Columbia V8W 2Y2, Canada.


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 mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein 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 mtCB1 receptors 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.

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