Prolonged incubation with Δ⁹-tetrahydrocannabinol but not with cannabidiol induces synaptic alterations and mitochondrial impairment in immature and mature rat organotypic hippocampal slices

Cannabis derivatives are among the most widely used psychoactive substances in the world, which leads to growing medical concerns regarding its chronic use and abuse especially among adolescents. Exposure to THC during formative years produces long-term behavioral alterations that share similarities with symptoms of psychiatric and neurodevelopmental disorders. In this study, we have analyzed the functional and molecular mechanisms that might underlie these alterations. Rat organotypic hippocampal slices were cultured for 2 days (immature) or 10 days (mature) in vitro and then exposed for 7 days to THC (1 µM) or CBD (1 µM). At the end of the treatment, slices were analyzed by Western blotting, electrophysiological recordings, RT-PCR, and fluorescence microscopy to explore the molecular and functional changes in the hippocampus. A prolonged (7-day) exposure to THC reduced the expression levels of pre- (synaptophysin, vGlut1) and post-synaptic (PSD95) proteins in both immature and mature slices, whereas CBD significantly increased the expression levels of PSD95 only in immature slices. In addition, THC significantly reduced the passive properties and the intrinsic excitability of membranes and increased sEPSCs in CA1 pyramidal cells of immature but not mature slices. Exposure to both cannabinoids impaired mitochondrial function as detected by the reduction of mRNA expression levels of mitobiogenesis genes such as VDAC1, UCP2, and TFAM. Finally, THC but not CBD caused tissue disorganization and morphological modifications in CA1 pyramidal neurons, astrocytes and microglia in both immature and mature slices. These results are helpful to explain the specific vulnerability of adolescent brain to the effects of psychotropic cannabinoids.