Long-term consequences of cannabinoid receptor activation during adolescence on PFC network activity and cognitive functions

Cannabis consumption, particularly among adolescents, has surged over the last decades. Adolescence is a critical period for brain development during which the prefrontal cortex (PFC) completes its maturation. There is strong evidence that the endocannabinoid system is a key regulator of brain development and of maturation of the PFC during adolescence. However, whether chronic cannabinoid receptor activation during this stage of development has long-term consequences for PFC function and associated behaviors remains unexplored. Here we show that repeated injection of cannabinoid receptor agonist WIN55,212-2 during adolescence caused long-lasting changes in intrinsic excitability and excitatory and inhibitory conductances of layer 5 pyramidal neurons of infralimbic and prelimbic PFC areas of female mice, but not of male mice. Correspondingly, we observed an increase in cognitive flexibility of WIN55,212-2 treated adult female mice, while cognitive performance of male mice was unaffected. In conclusion, our results show that repeated cannabinoid receptor activation during adolescence interferes with the normal development of the PFC in a sex-dependent manner. We observed long-term consequences for PFC network excitability and for the higher order cognitive functions it fulfills. We believe our study underscores the sex-specific long-term risks of cannabis use during adolesecence.