Serotonergic Modulation in Absence Epilepsy: The Role of Thalamo-cortical Networks and 5-hydroxytryptamine Receptors

Absence epilepsy is characterized by brief nonconvulsive seizures and generalized spike-and-wave discharges (SWDs) generated within distributed cortico-thalamo-cortical networks. Although the roles of T-type calcium channels, GABAergic inhibition, and network synchronization are well established, serotonergic modulation of these circuits remains incompletely defined. This review integrates evidence from genetic and pharmacological animal models, receptor signaling and distribution studies, human neurophysiological and neuroimaging investigations, clinical observations, and emerging receptor-selective approaches. The available evidence indicates that serotonergic effects are determined by receptor subtype, anatomical and cellular localization, developmental stage, and experimental model. Activation of 5-HT ₂ C receptors generally suppresses SWDs, potentially by reducing excessive tonic GABA-A inhibition in thalamocortical neurons, whereas 5-HT ₇ receptor antagonism reduces SWDs in WAG/Rij rats, although its underlying cellular mechanism remains uncertain. In contrast, 5-HT ₁ A receptor modulation produces bidirectional, model-dependent effects, and thalamic 5-HT ₂ A receptor activation may either suppress or facilitate absence activity depending on the functional state of the network. Evidence concerning 5-HT ₃ , 5-HT ₄ , 5-HT ₅ , and 5-HT ₆ receptors is sparse. Globally acting serotonergic antidepressants also show heterogeneous effects in preclinical models, and human data do not establish an antiabsence benefit. Preliminary findings from an open-label Phase 2 study of the selective 5-HT ₂ C agonist BMB-101 are insufficient to determine clinical efficacy. Overall, receptor-selective serotonergic mechanisms offer mechanistic insight and potential investigational targets, particularly 5-HT ₂ C and 5-HT ₇ receptors; however, current evidence does not support altering established absence epilepsy treatment. Controlled clinical studies and developmentally appropriate translational models are required.