Study of new potential therapeutic approaches for the Rett syndrome in murine models

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in either the MECP2 or CDKL5 gene. Currently there is no cure for this devastating disorder. The present thesis investigated the potential therapeutic efficacy of two different molecules on RTT mice carrying mutations in MeCP2 or Cdkl5 gene: LP-211, an agonist of serotonin receptor 7 (5-HT7R) and Cannabidivarin (CBDV), new phytocannabinoid under investigation in the clinical setting, which targets the G protein-coupled receptor 55 (GPR55). Our results demonstrate that LP-211 rescue a wide range of behavioural and brain molecular alterations both in MeCP2 and Cdkl5-mutated mice. New clues on the possible mechanism of LP-211 action are provided. The present thesis also demonstrates that in MeCP2-mutated mice the chronic CBDV treatment rescues many important behavioural alterations; moreover, we suggest a possible mechanism of action for CBDV, proposing brain GPR55 as a new pharmacological target for RTT treatment. Despite further studies are needed to clarify the link between RTT and the serotoninergic and/or the endocannabinoid system, the present thesis suggests innovative targets and two promising pharmacological approaches for the treatment of patients affected by this severe disorder.