Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB1 cannabinoid receptor. In contrast, the CB2 cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB2-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB1-mediated psychoactive effects. CB2 receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB2 receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB2 receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB2-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB2-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB2-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB2 cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.—Palazuelos, J., Aguado, T., Egia, A., Mechoulam, R., Guzma´n, M., Galve-Roperh, I. Nonpsychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. F
