Cannabinoid and adenosine A_2A receptor crosstalk regulates postnatal and adult hippocampal neurogenesis

Adult neurogenesis is a tightly regulated process affected by both cannabinoid receptors (CB₁ and CB₂) 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.

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.

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 CB₂ or A_2A receptors promoted self-renewing divisions of hippocampal-derived neural progenitor cells. A_2A receptor antagonism impaired CB₂ receptor-mediated effects, whereas CB₁/CB₂ antagonism blocked A_2A-mediated effects. Co-activation of CB₁ or CB₂ receptors with A_2A receptors promoted a significant increase in cell proliferation. Notably, the proneurogenic effects mediated by CB₁ or CB₂ receptor agonists were blocked by A_2A receptor antagonism, while A_2A receptor-mediated actions on neuronal differentiation were blocked by CB₁ or CB₂ receptor antagonists. Finally, receptor-binding assays showed that A_2A and CB₁ receptors form heteromers in the mouse hippocampus, suggesting that their functional interaction may involve direct receptor-receptor crosstalk.

Taken together, these findings suggest a crosstalk between the adenosinergic and cannabinergic systems responsible for regulating hippocampal progenitor dynamics. The identification of CB₁-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.