Perturbations of CB1 receptor signalling during adolescence impair cortical myelination in female rats

Abstract

The constant increase in cannabis use among adolescents raises concerns about its potential neurobehavioral effects. Adolescence is a critical period for brain development, involving significant changes in grey and white matter. Grey matter decreases as the brain undergoes synaptic pruning, while white matter increases due to myelination. Cannabis use during this developmental window, particularly its active ingredient delta-9-tetrahydrocannabinol (THC), may disrupt these processes, increasing the risk of developing psychiatric disorders later in life. While the impact of THC on grey matter has been explored, the specific role of CB1 receptors as well as the effect of THC exposure in adolescent myelination remain unclear. This study investigates how CB1 receptor blockade and THC exposure during adolescence affect myelination in the prefrontal cortex of female rats. Blocking CB1 receptors during adolescence hindered myelination in the prefrontal cortex. Behaviourally, this disruption in myelin formation was associated with increased risk-taking behaviour. Notably, our data suggest that alterations in the AKT/Hippo/YAP signalling pathway may play a crucial role in mediating these effects. Supporting the involvement of the endocannabinoid system in cortical myelination during adolescence, we found that administering exogenous THC impaired myelin formation only when given during early to mid-adolescence. Moreover, when a more intensive THC exposure protocol was applied during this developmental period, the effects on myelination were long-lasting and persisted into adulthood. Overall, these data support a role for CB1 receptors in shaping cortical myelination in adolescent female rats and show that adolescent exposure to THC might adversely impact this developmental process.