A cannabinoid link between mitochondria and memory
Abstract
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 (mtCB 1) 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 mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i 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 mtCB 1 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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CB1 receptors are expressed in the mitochondrial membrane, where they act on the regulation of energy metabolism and mitochondrial functions.
“Importantly, CB1 receptors have been shown to be expressed in the mitochondrial membrane, where they act on the regulation of energy metabolism and mitochondrial functions25–27.”
CB1 receptors are expressed in mitochondria where they regulate energy metabolism and mitochondrial functions.
“Recently, CB1 receptors were shown to be expressed in mitochondria where they regulate energy metabolism and mitochondrial functions25–27.”
Recent evidence implicates glial and mitochondrial CB1R in eCB-mediated mnemonic processes, together with a known role for astrocytes and mitochondria in stress- and anxiety-related processes.
“recent evidence for glial (Han et al., 2012) and mitochondrial CB1R (Hebert-Chatelain et al., 2016) in eCB-mediated mnemonic processes, together with a known role for astrocytes (Oliveira et al., 2015) and mitochondria (Manji et al., 2012) in stress- and anxiety-related processes.”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hebert-Chatelain et al., 2016
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- Authors
- Hebert-Chatelain, E., Desprez, T., Serrat, R., Bellocchio, L., Soria-Gomez, E., Busquets-Garcia, A., Pagano Zottola, A. C., Delamarre, A., Cannich, A., Vincent, P., Varilh, M., Robin, L. M., Terral, G., García-Fernández, M. D., Colavita, M., Mazier, W., Drago, F., Puente, N., Reguero, L., Elezgarai, I., Dupuy, J.-W., Cota, D., Lopez-Rodriguez, M.-L., Barreda-Gómez, G., Massa, F., Grandes, P., Bénard, G., & Marsicano, G.
- Affiliations
- Université de Bordeaux (FR)
- Universidad Complutense de Madrid (ES)
- University of the Basque Country (ES)
- University of Catania (IT)
- Corresponding author
- Marsicano, Giovanni
- ORCID
- Venue
- Nature
- Published
- 2016-11
- Volume
- 539
- Issue
- 7630
- Pages
- 555-559
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2551139658
- Cited by
- 434
- References
- 50
- Citations by year
- 2026: 18 · 2025: 41 · 2024: 37 · 2023: 47 · 2022: 61 · 2021: 61 · 2020: 51 · 2019: 36 · 2018: 44 · 2017: 35 · 2016: 2
- FWCI
- 31.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-13-BSV4-0006, ANR-10-LABX-0043)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cannabinoids, CB1 receptor, memory impairment, amnesia, hippocampus, mitochondrial bioenergetics, synaptic transmission, Gi protein, soluble adenylyl cyclase, protein kinase A, NDUFS2, mitochondrial electron transport chain, cellular respiration, cognitive function
- MeSH terms
- Adenylyl Cyclases, Animals, Cannabinoids, Electron Transport, Energy Metabolism, Female, Hippocampus, Male, Memory, Memory Disorders, Mitochondria, NADH Dehydrogenase, Synaptic Transmission, Oxidative Phosphorylation, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Cell Respiration, GTP-Binding Protein alpha Subunits, Gi-Go, Receptor, Cannabinoid, CB1, Mitochondrial Membranes, Mice
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