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 (Ca²⁺) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A₁ and A_2A receptors (A₁R, A_2AR), 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-A_2AR or CB1R-A₁R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca²⁺ transients increased and decreased when A₁R and A_2AR 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 A_2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca²⁺ level elevations, CB1R activation decreases LTP, which is not modified by A₁R or A_2AR. 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.