“Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CB₁R and CB₂R) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB₁R and CB₂R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation). We focused on a putative crosstalk between CB₁R and CB₂R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CB₁R or CB₂R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB₁R and CB₂R. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CB₁R selective activation. However, either CB₁R or CB₂R selective antagonists abolished the effect of the CB₁R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB₁R or CB₂R selective agonists and blocked by either CB₁R or CB₂R selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CB₁R and CB₂R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.”