Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome.

The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with abnormal activity of the 5-HT transporter leading to altered 5-HT brain levels. We provide an update on therapeutic effects exerted by drugs modulating serotonergic transmission on Fragile X patients and animal models. The enhancement of serotonergic transmission using Selective Serotonin Reuptake Inhibitors (SSRIs) corrected mood disorders and language deficits in Fragile X patients. In Fmr1 KO mice, a model of Fragile X Syndrome, selective 5-HT7 receptor agonists rescued synaptic plasticity, memory and stereotyped behavior. In addition, drugs specifically acting on 5-HT1A, 5-HT2 and 5-HT5 receptor subtypes were able to correct, respectively, epilepsy, learning deficits and hyperactivity in different Fragile X animal models. In conclusion, the SSRI treatment of Fragile X patients improves mood and language; in parallel, studies on animal models suggest that compounds selectively acting on distinct 5-HT receptor subtypes might provide a targeted correction of other Fragile X phenotypes, and thus should be further tested in clinical trials for future therapy.