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

Rui S. Rodrigues, Filipa F. Ribeiro, Filipa Ferreira, Sandra H. Vaz, Ana M. Sebastião, Sara Xapelli
Frontiers in Pharmacology. 2017-08-10; 8:
DOI: 10.3389/fphar.2017.00516

1. Front Pharmacol. 2017 Aug 10;8:516. doi: 10.3389/fphar.2017.00516. eCollection
2017.

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

Rodrigues RS(1)(2), Ribeiro FF(1)(2), Ferreira F(1)(2), Vaz SH(1)(2), Sebastião
AM(1)(2), Xapelli S(1)(2).

Author information:
(1)Instituto de Farmacologia e Neurociências, Faculdade de Medicina,
Universidade de LisboaLisboa, Portugal.
(2)Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de
LisboaLisboa, Portugal.

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.