 Figure 7. Model illustrating the possible mechanism induced in the prefrontal cortex by chronic consumption of THC during adolescence that leads to long-lasting cognitive impairment. Left panel: physiological condition. Right panel: chronic consumption of THC during adolescence induces an overactivation of prefrontal CB1 receptors that are mainly located on GABAergic terminals. As previously established in adult mice that received an acute THC treatment (Puighermanal et al., 2009), this might lead to a decrease in GABA release and, subsequently, to an increase in the glutamatergic tone. Likewise, adolescent THC consumption might also increase serotoninergic tone leading to a sustained activation of 5-HT6 receptor located on pyramidal neurons which is prerequisite for the long-lasting stimulation mTOR signaling pathway. This in turn leads to an alteration in intrinsic neuronal properties and cognitive deficits in adulthood. The non-physiological activation of mTOR and resulting imbalance in the excitatory/inhibitory equilibrium during adolescence might also interfere with maturational events occurring in the adolescent prefrontal cortex leading to a persistent rearrangement of cortical networks affecting the serotonergic system itself and, ultimately, to a persistent mTOR activation. For the clarity of the figure, CB1 receptors were only represented on GABAergic terminals. The presence of GABA-A receptors onto glutamatergic and serotoninergic terminals were previously suggested in (Alle and Geiger, 2007; Ruiz et al., 2010; Yamamoto et al., 2011) and (Cerrito et al., 1998), respectively. Expanded View Figure Legends 