Adenosine receptors are the on‐and‐off switch of astrocytic cannabinoid type 1 (CB1) receptor effect upon synaptic plasticity in the medial prefrontal cortex

© 2024 The Authors. GLIA published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1R, A2AR), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2AR or CB1R-A1R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca2+ transients increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. CB1R activation leads to an enhancement of long-term potentiation (LTP) in the mPFC, under the control of A1R but not of A2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca2+ level elevations, CB1R activation decreases LTP, which is not modified by A1R or A2AR. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling. This work was supported by the Fundaçao para a Ciência e para a Tecnologia (FCT) (grant PTDC/MED-FAR/30933/2017 to AMS, PD/BD/150342/2019 to JG-R and SFRH/BD/147277/2019 to SC-P), by the International Society for Neurochemistry (Carer Development Grant 2021 to SHV), the European Union (H2020-WIDESPREAD-05-2017-Twinning (EpiEpinet), grant agreement 952455, to AMS and SHV), the Spanish Ministry for Science, Innovation and Universities (MCIN/AEI/10.13039/501100011033) and the “ERDF A way of making Europe” (grant PID2021-122586NB-I00 to MN and PID2021-126600OB-I00 to RF), and the Fundación Tatiana Pérez de Guzmán el Bueno (PhD grant to JSR).