Abstract

Cannabis is the most widely used illicit drug, particularly during adolescence. Its consumption disrupts glutamate homeostasis and synaptic plasticity in the nucleus accumbens (NAc). Here, we identify a functionally distinct accumbal astrocytic ensemble, associated with the ventral hippocampus–NAc (vHip→NAc) circuit, that is critical for tetrahydrocannabinol (THC)-induced synaptic and behavioral impairments. We employed the AstroLight tool to selectively manipulate this astrocytic ensemble. Our findings reveal that THC increases astrocytic calcium activity and glutamatergic tone within the NAc. These glutamatergic alterations are absent in astrocyte-specific p38α knockout mice, implicating p38α signaling in astrocyte-mediated plasticity. Astrocytic glutamate release within the vHip→NAc ensemble is required for THC-induced cognitive deficits, and targeted attenuation of THC-induced calcium activity in this ensemble prevents spatial learning and synaptic plasticity impairments. These results highlight a critical role for astrocytic ensembles in shaping behavior and emphasize their potential as therapeutic targets for mitigating the cognitive consequences of THC exposure.

Data availability

All data generated in this study are provided in the Source Data file. Details on the statistical tests are provided in Supplementary Data 1. Source data are provided with this paper.

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Acknowledgements

We are grateful to Gertrudis Perea, Alfonso Araque, and Eduardo Martín for their valuable support and insightful discussions. We also thank Delphine Gonzales, Nathalie Aubailly, Elizabeth Huc, and all the staff at the Animal Facility of the NeuroCentre Magendie, as well as at the Cajal Institute, for their assistance. This work was supported by the following grants: PID2021-122586NB-I00 and PID2024-156577NB-I00, funded by MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund (ERDF), “A way of making Europe,” to M.N.; PRX23/00185, under Estancias de profesores e investigadores senior en centros extranjeros “Salvador de Madariaga” program to M.N.; FPU19/1667 and EST23/720, funded by the Spanish Ministry of Universities (MIU), to C.M.-M.; Fundación Tatiana Pérez de Guzmán el Bueno to J.S.R. Additional funding was provided by IT1620-22 from the Basque Government, RD21/0009/0006 from the Instituto de Salud Carlos III (ISCIII) and the European Union through the NextGenerationEU and the Recovery and Resilience Mechanism, to P.G., as well as RD24/0003/0027, co-funded by ISCIII and the European Union. We also acknowledge support from the European Research Council (Micabra, ERC-2017-AdG-786467), to G.M.; Fondation pour la Recherche Médicale (DRM20101220445), to G.M.; Agence Nationale de la Recherche (CaMeLS ANR-23-CE16-0022-01 and Hippobese ANR-23-CE14-0004-03), to G.M.; and the French Government, through the University of Bordeaux’s IdEx Investments for the Future–France 2030 program / GPR BRAIN_2030, to G.M. The RNAscope experiments by J.M.A were supported by unrestricted funds in the form of the Eleanor I. Leslie Chair in Neuroscience to B.S.K.

Author information

Authors and Affiliations

Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain

Cristina Martín-Monteagudo, Javier Sánchez Romero & Marta Navarrete 1.

Department of Physiology, University of California Los Angeles, Los Angeles, CA, USA

Julia M. Adams & Baljit S. Khakh 1.

Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain

Nagore Puente & Pedro Grandes 1.

Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Spain

Nagore Puente & Pedro Grandes 1.

Université de Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France

Giovanni Marsicano & Ana Covelo 1.

CINBIO, University of Vigo, Vigo, Spain

Ana Covelo 1.

Galicia Sur Health Research Institute (IISGS), Laboratory of Neuroscience, Vigo, Spain

Ana Covelo 1.

Centro de Neurociencias Cajal, Consejo Superior de Investigaciones Científicas, Alcalá de Henares, Spain

Marta Navarrete

Authors

1. Cristina Martín-Monteagudo
2. Javier Sánchez Romero
3. Julia M. Adams
4. Nagore Puente
5. Pedro Grandes
6. Giovanni Marsicano
7. Ana Covelo
8. Baljit S. Khakh
9. Marta Navarrete

Contributions

C.M.-M. performed most of the experiments with assistance from J.S.R.; J.S.R. performed glutamatergic current recordings; J.M.A. performed the RNAscope experiments supervised by B.S.K.; RNAscope experiments were analyzed by C.M.-M. under the supervision of M.N.; N.P. conducted the EM study supervised by P.G.; A.C. and G.M. designed and supervised the CB1R-KO experiments; all authors discussed the data; M.N. conceived and designed the study and wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Marta Navarrete.

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Martín-Monteagudo, C., Sánchez Romero, J., Adams, J.M. et al. An astrocytic ensemble at vHip-NAc synapses modulates cognitive impairments induced by chronic tetrahydrocannabinol exposure. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67166-w

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Received: 10 February 2025

Accepted: 24 November 2025

Published: 09 December 2025

DOI: https://doi.org/10.1038/s41467-025-67166-w