Identifying therapeutic targets for the treatment of Fragile X Syndrome : Implications for Autism Spectrum Disorders

Fragile X syndrome (FXS) is a neurodevelopmental disorder due to an X-linked mutation in the FMR1 gene that results in intellectual disability (ID), autism spectrum disorder (ASD), anxiety, attention deficit hyperactivity disorder (ADHD) and sensory processing deficits. There is substantial overlap between FXS and ASD as approximately 30 to 50% of individuals diagnosed with FXS also meet the diagnostic criteria for ASD. Furthermore FXS-ASD patients represent approximately 5% of all cases of ASD. Since there is currently no targeted therapeutic approach, novel pharmacological agents addressing the neurobiological underpinnings of these disorders are crucially needed. Due to the overlap between the two conditions, systems which are disrupted in FXS and ASD patients may provide targets for treating the ASD symptoms observed in FXS-ASD patients and some non-syndromic ASD patients. FMRP, the protein lost by the FMR1 mutation, is a potent regulator of the endocannabinoid system (ECS) and BKCa channels. These function to regulate presynaptic excitability. Dysfunction in these systems is found in FXS patients and some ASD patients. The presynaptic role of these agents conceptualizes the “presynaptic hypothesis of FXS-ASD”. This project used genetic and pharmacological approaches which target FMRP, the ECS or BKCa channels in combination with an extensive behavioral characterization of FXS and ASD-relevant phenotypes, in order to assess the therapeutic value of these targets. This work demonstrates that the ECS and BKCa channels contribute to behavioral domains affected in neurodevelopmental disorders and offer several targets for therapeutics which should be explored.