Activation of serotonin type 7 (5-HT7) receptors as a novel therapeutic strategy in Fragile X Syndrome

Fragile X Syndrome is a genetic disease causing intellectual disability, mood disorders, epilepsy and autism. Fragile X patients display alterations in the shape and organization of brain synapses, the structures by which nerve cells communicate. Synapse malfunction was evidenced in Fmr1 KO mice, an animal model of fragile X syndrome: in particular, synaptic plasticity (persistent changes in the efficacy of synaptic transmission) is pathologically altered in the frontal cortex and hippocampus, the main brain regions responsible for learning and memory. We have recently shown that serotonin (5-HT), a neurotransmitter controlling many physiological functions, is able to rescue synaptic plasticity in the hippocampus of Fmr1 KO mice. We have identified a receptor named 5-HT7 as responsible for serotonin effect. 5-HT7 receptors have been discovered relatively recently; for these receptors, selective blockers are available whereas putative agonists (molecules able to activate the receptor) are still under investigation. In the present project, three research units with complementary expertise will perform a preclinical study on Fmr1 KO mice in the aim to 1) find out the action mechanism of 5-HT7 receptors; 2) test if in vivo administration of a 5-HT7 receptor agonist can correct typical abnormal features of fragile X syndrome, namely abnormal synaptic plasticity, altered synapse shape, enhanced sensitivity to seizures and learning deficits. In addition, we will synthesize and characterize new 5-HT7 receptor agonists with improved pharmacokinetic properties (chemical and metabolic stability in vivo and ability to penetrate the brain) and select the most suitable for systemic administration. Results from our experiments will indicate if new molecules selectively activating 5-HT7 receptors can be considered as novel pharmacological tools for the therapy of fragile X syndrome.