Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP1,2,3,4. Acute cannabinoid intoxication induces amnesia in humans and animals5,6, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity7,8,9. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established1,2, 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 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
We thank D. Gonzales,N. Aubailly and all the personnel of the Animal Facility of the NeuroCentre Magendie, M. Biguerie of the technical service of the NeuroCentre Magendie, the personnel from the Bordeaux Imaging Center and V. Morales for continuous help. We thank G. Manfredi (Cornell University) for the sAC–HA, A. Feliciello (University of Napoli) for anti-AKAP121 antiserum and for AKAP121 shRNA, and M. Montcouquiol, N. Piguel (INSERM U1215, Bordeaux) and R. Rossignol (University of Bordeaux) for help with experiments. We thank F. Francia, P. V. Piazza, A. Bacci, G. Ferreira, F. Chaouloff and M. Guzman for critical reading and the members of Marsicano’s laboratory for discussions. This work was supported by INSERM (G.M., D.C.), EU–Fp7 (PAINCAGE, HEALTH-603191, G.M. and FP7-PEOPLE-2013-IEF-623638, A.B.-G.), European Research Council (Endofood, ERC–2010–StG–260515 and CannaPreg, ERC-2014-PoC-640923, G.M.), Fondation pour la Recherche Medicale (DRM20101220445, G.M., SPF20121226369, R.S. and ARF20140129235, L.B.), Fondation pour la Recherche en Psychiatrie et en Santé Mentale (FRPSM, G.M.), Human Frontiers Science Program (RGP0036/2014, G.M.), Region Aquitaine (G.M.), AFM Telethon Trampoline Grant (16474, G.B.), Agence Nationale de la Recherche (ANR Blanc NeuroNutriSens ANR-13-BSV4-0006, G.M., D.C., BRAIN ANR-10-LABX-0043, G.M., D.C., F.M. and ANR-10-IDEX-03-02, A.B.-G.), Dulbecco Telethon Institute post-doc fellowship (E.H.-C.), NSERC (RGPIN-2015-05880, E.H.-C.), Fyssen Foundation (E.S.-G.), EMBO post-doc fellowship (L.B.), CONACyT (E.S.-G.), Zabalduz pre-doc fellowship (M.D.G.-F.), the Basque Government (IT764-13, P.G.), MINECO/FEDER (SAF2015-65034-R, P.G.), University of the Basque Country (UPV/EHU UFI11/41, P.G.), Red de Trastornos Adictivos—Instituto de Salud Carlos III (RD12/0028/0004, RD16/0017/0012, P.G.).
Extended data figures
Effect of the CB1 receptor agonist HU210 on mitochondrial mobility in CB1-/- hippocampal neurons re-expressing CB1. Representative time-lapse live imaging of axonal mitochondria before and after treatment of HU210 (1µM) for 15 min in a primary hippocampal neuron from CB1-/- mice, transfected with CB1-GFP. See Fig. 1e.
Re-expression of DN22-CB1 fails to rescue the HU210-dependent decrease of mitochondrial mobility in CB1-/- hippocampal neurons. Representative time-lapse live imaging of axonal mitochondria before and after treatment of HU210 (1µM) for 15 min in a primary hippocampal neuron from CB1-/- mice, transfected with DN22-CB1-GFP. See Fig. 1e.
Representative time-lapse live imaging of axonal mitochondria before and after treatment of HU210 (1µM) and vehicle for 15 min in a primary hippocampal neuron from CB1-/- mice, transfected with CB1-GFP. See Fig. 3b.
The sAC inhibitor KH7 blocks the reduction of mitochondrial mobility induced by HU210. Representative time-lapse live imaging of axonal mitochondria before and after treatment of HU210 (1µM) for 15min in the presence of KH7 (5µM) in a primary hippocampal neuron from CB1-/- mice, transfected with CB1-GFP. See Fig. 3b.