Interaction between Cannabinoid Type 1 and Type 2 Receptors in the Modulation of Subventricular Zone and Dentate Gyrus Neurogenesis.

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.