期刊
NATURE
卷 539, 期 7630, 页码 555-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature20127
关键词
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资金
- INSERM
- EU-Fp7 (PAINCAGE [HEALTH-603191, FP7-PEOPLE-2013-1EF-623638]
- European Research Council (Endofood) [ERC-2010-StG-260515, ERC-2014-PoC-640923]
- Fondation pour la Recherche Medicate [DRM20101220445, SPF20121226369, ARF20140129235]
- Fondation pour la Recherche en Psychiatrie et en Sante Mentale (FRPSM)
- Human Frontiers Science Program [RGP0036/2014]
- Region Aquitaine
- AFM Telethon Trampoline Grant [16474]
- Agence Nationale de la Recherche (ANR Blanc NeuroNutriSens) [ANR-13-BSV4-0006]
- BRAIN [ANR-10-LABX-0043, ANR-10-IDEX-03-02]
- Dulbecco Telethon Institute post-doc fellowship
- NSERC [RGPIN-2015-05880]
- Fyssen Foundation
- EMBO post-doc fellowship
- CONACyT
- Zabalduz pre-doc fellowship
- Basque Government [11764-13]
- MINECO/FEDER [SAF2015-65034-R]
- University of the Basque Country [UPV/EHU UF111/41]
- Red de Trastornos Adictivos Instituto de Salud Carlos III [RD12/0028/0004, RD16/0017/0012]
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP(1-4). Acute cannabinoid intoxication induces amnesia in humans and animals(5,6), and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB(1)) can directly alter mitochondrial energetic activity(7-9). Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established(1,2), 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 CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB(1) receptors signal through intra-mitochondrial G alpha(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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