Δ-9-Tetrahydrocannabinol treatment during adolescence and alterations in the inhibitory networks of the adult prefrontal cortex in mice subjected to perinatal NMDA receptor antagonist injection and to postweaning social isolation.

The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.