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

The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca 2+ ) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A 1 and A 2A receptors (A 1 R, A 2A R), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca 2+ signaling occurs through CB1R‐A 2A R or CB1R‐A 1 R heteromers that ultimately impact mPFC synaptic plasticity. CB1R‐mediated Ca 2+ transients increased and decreased when A 1 R and A 2A R 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 A 1 R but not of A 2A R. Notably, in IP3R2KO mice, that do not show astrocytic Ca 2+ level elevations, CB1R activation decreases LTP, which is not modified by A 1 R or A 2A R. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A 1 R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca 2+ signaling.