Cannabinoid and adenosine A 2A receptor crosstalk regulates postnatal and adult hippocampal neurogenesis
Rui S. Rodrigues, Adam Armada‐Moreira, Laura Gómez‐Acero, Filipa F. Ribeiro, Francisco M. Mouro, Ana M. Sebastião, Francisco Ciruela, Ester Aso, Sara XapelliBackground and purpose
Adult neurogenesis is a tightly regulated process affected by both cannabinoid receptors (CB 1 and CB 2 ) and adenosine 2A (A 2A ) receptors, both of which modulate neural progenitor cell activity. While emerging evidence suggests an interaction between these neuromodulatory systems, the extent and mechanism of their interplay in regulating neurogenesis remain unclear.
Experimental approach
Using a combination of in vivo and in vitro approaches together with pharmacological and receptor/binding assays, we investigated the crosstalk between A 2A and CB receptors in regulating hippocampal neurogenesis.
Key results
In vivo administration of WIN55212‐2, a non‐selective cannabinoid receptor agonist, increased hippocampal cell proliferation and immature neuron formation, an effect abolished by istradefylline, a selective A 2A receptor antagonist. In vitro , activation of CB 2 or A 2A receptors promoted self‐renewing divisions of hippocampal‐derived neural progenitor cells. A 2A receptor antagonism impaired CB 2 receptor‐mediated effects, whereas CB 1 /CB 2 antagonism blocked A 2A ‐mediated effects. Co‐activation of CB 1 or CB 2 receptors with A 2A receptors promoted a significant increase in cell proliferation. Notably, the proneurogenic effects mediated by CB 1 or CB 2 receptor agonists were blocked by A 2A receptor antagonism, while A 2A receptor‐mediated actions on neuronal differentiation were blocked by CB 1 or CB 2 receptor antagonists. Finally, receptor‐binding assays showed that A 2A and CB 1 receptors form heteromers in the mouse hippocampus, suggesting that their functional interaction may involve direct receptor‐receptor crosstalk.
Conclusions and implications
Taken together, these findings suggest a crosstalk between the adenosinergic and cannabinergic systems responsible for regulating hippocampal progenitor dynamics. The identification of CB 1 –A 2A receptor heteromerization provides new insights into the molecular basis of neurogenic modulation and highlights a promising avenue for the development of novel proneurogenic therapeutic strategies.