Abstract/Summary

Tuberous Sclerosis Complex (TSC) is a rare genetic disease caused by TSC1 or TSC2 mutations, characterized by overactivation of mechanistic target of rapamycin (mTOR). Among others, this leads to increased cell growth, altered cellular structure and migration. Consequently, TSC patients exhibit multiorgan tumours, namely in the brain, with neurological and neuropsychiatric manifestations affecting the majority of individuals. Central nervous system (CNS) alterations are a significant contributor to decreased quality of life and increased morbidity and caregiver dependence. Although pharmacological options are available to manage specific CNS features of TSC, these are limited and not curative, creating a high demand for new entities that address these symptoms. In the search for novel compounds that target CNS manifestations in TSC, I focused on cannabidiol, a phytocannabinoid present in Cannabis, seeking out to explore and identify which CBD effects could contribute positively to the management of TSC. With a zebrafish model of TSC, I demonstrated that CBD reduced the activation of the mTOR downstream molecule rpS6, cell size and anxiety-like behaviour. Using a rat model of TSC, the Eker rat, I described a novel cerebellar characterization and identified mutation-dependent cell size and density alterations, modified by CBD. Following long-term CBD administration and behavioural analysis, I corroborated the mild phenotype of the Eker rat and the action of CBD on rpS6. The Eker mutation also appeared to have no effect on seizure susceptibility following shortterm CBD treatment. In both cases, mutation and treatment revealed minimal disease-modifying effects. The results presented in this thesis provide novel information on the in vivo effects of CBD in the presence of TSC mutations and additional insight on the appropriateness of TSC models to explore CNS manifestations. The data presented is a valuable contribution to the development of novel interventions for TSC and to the study of TSC itself.