Cannabis use can lead to effects in the brain that impact the normal functioning of users, including problems in sociability. The present paper - available now online and on July 23rd in press - explores how astrocytes, the most abundant brain cells, play a key role on the metabolic dysfunction associated with high doses of THC which results in decreased sociability in mice. The huge collaborative effort between the teams of Juan Bola¬ños in Salamanca and the Marsicano team allowed merging the expertise of the spanish team in brain bioenergetics and the expertise of our team in mouse in vivo experiments to better understand a novel way in which cannabinoids affect the brain.
In 2012, we showed that cannabinoid receptors are not only present on the cell membrane, but can also be present at mitochondria, the intracellular organelles whose role is to provide the cells with the energy they need . This new study comes after showing that cannabinoid receptors are also located on the astroglial mitochondrial membranes . These glial cells play a key role in brain energy metabolism as they transform glucose into lactate, which acts as "food" for neurons. Based on this, the paper explores how mitochondrial CB1 receptors impact astroglial bioenergetics both in vitro and in vivo. We first used astrocyte cultures where we observed that persistent activation of mitochondrial cannabinoid receptors destabilizes mitochondrial Complex I through the specific modulation of the phosphorylation status of NDUFS4, a C-I subunit important for its stability. A decrease of Complex stability decreases mitochondrial ROS levels in astrocytes affecting the activity of the transcription factor HIF1, a key regulator of glycolysis which leads to a dysfunction of glucose metabolism with a reduction of astroglial lactate levels. We next used a co-culture strategy to demonstrate that the astroglial bioenergetic alterations produced by the persistent activation of mitochondrial cannabinoid receptors resulted in an enhancement of mitochondrial ROS in neurons, among other bioenergetic alterations. In vivo, we used genetic approaches and NMR and FACS strategies to confirm the effects observed in cell cultures. We show that THC administration in mice reduces glucose-lactate conversion impacting the functioning of neurons by altering similar bioenergetic alterations. Interestingly, THC produces a persistent social interaction impairment still present 24 hours after administration that is not present in mice lacking astroglial CB1 receptors and is reversed by 1) manipulating the phosphorylation status of NDUFS4, 2) reducing neuronal mitochondrial ROS levels or 3) lactate supplementation. These findings not only suggest possible novel therapeutic targets to tackle negative effects of cannabis consumption or other conditions with social impairments, but highlight the fact that the interaction between different brain cells might be also very important to understand how the brain control our actions.
You can check the News and Views written about this study, which summarizes the main points of the paper in a very comprehensive way: https://www.nature.com/articles/d41586-020-01975-5
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 Bénard, G., Massa, F., Puente, N., Lourenço, J., Bellocchio, L., Soria-Gómez, E., Matias, I., Delamarre, A., Metna-Laurent, M., Cannich, A., Hebert-Chatelain, E., Mulle, C., Ortega-Gutiérrez, S., Martín-Fontecha, M., Klugmann, M., Guggenhuber, S., Lutz, B., Gertsch, J., Chaouloff, F., López-Rodríguez, M. L., … Marsicano, G. (2012). Mitochondrial CB₁ receptors regulate neuronal energy metabolism. Nature neuroscience, 15(4), 558–564. DOI: 10.1038/nn.3053
 Gutiérrez-Rodríguez, A., Bonilla-Del Río, I., Puente, N., Gómez-Urquijo, S. M., Fontaine, C. J., Egaña-Huguet, J., Elezgarai, I., Ruehle, S., Lutz, B., Robin, L. M., Soria-Gómez, E., Bellocchio, L., Padwal, J. D., van der Stelt, M., Mendizabal-Zubiaga, J., Reguero, L., Ramos, A., Gerrikagoitia, I., Marsicano, G., & Grandes, P. (2018). Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia, 66(7), 1417–1431. DOI: 10.1002/glia.23314