Compelling animal and human evidence suggests that serotonin plays an important role in the pathophysiology of epilepsy as it is involved in iperexcitability, epileptogenesis, seizure generation, depression and psychiatric disorders comorbid with epilepsy. Serotonin involvement in epilepsy is complex; the reasons are twofold i) epilepsy is in reality a spectrum disorder, and ii) serotonin effects vary from one form of epilepsy to another, due also to the different serotonin receptors involved. Here, we will focus on the role of serotonin and its 5-HT2 receptors in absence epilepsy. Our recent pharmacological experimental evidence in GAERS will be reviewed together with our preliminary optogenetic results. 5-HT2C receptor agonists may represent a new approach to interfere with seizure generation and seizure management. Our optogenetic experiments also indicate that by modulating rhythmic cortical activity, optogenetic stimulation of the serotonergic system may provide seizure control without the adverse effects induced by pharmacological activation of 5-HT2C receptors. Thus, targeting the serotonergic system could provide novel insights into the pathophysiological mechanisms of seizure generation and lead to potentially novel treatments.peer-reviewe
