Thalamic distribution and effects of 5-HT2C receptors on tonic GABAA inhibition and absence seizures: implications for treatment

Introduction: Childhood absence epilepsy (CAE) is associated with abnormal thalamocortical oscillations and enhanced GABAergic function in the ventrobasal (VB) thalamus, including increased extrasynaptic GABAA receptor–mediated tonic currents in thalamocortical (TC) neurons. Serotonin signaling modulates seizure activity in several epilepsy models, and activation of 5-HT2C receptors (5-HT2CRs) has been reported to exert anti-absence seizure effects, although the underlying cellular mechanisms remain unclear. Here, we examined the thalamic distribution of 5-HT2CRs and their functional impact on tonic GABAA inhibition and absence seizures. Methods: 5-HT2CR expression in the nucleus reticularis thalami (NRT) and VB was assessed by immunohistochemistry in adult Wistar rats, Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and their non-epileptic control strain (NEC). Whole-cell patch-clamp recordings were used to measure tonic GABAA currents in VB TC neurons in thalamic slices. In vivo EEG recordings in freely moving GAERS rats were performed to evaluate the effects of systemic administration of the 5-HT2CR agonist Ro 60-0175 on absence seizures. Results: No differences in 5-HT2CR expression were observed in the NRT across strains. In the VB, receptor expression was lowest in GAERS and highest in Wistar rats compared with NEC. Tonic GABAA currents in TC neurons were larger in GAERS than in Wistar or NEC rats. Activation of 5-HT2CRs with Ro 60-0175 reduced tonic GABAA currents in TC neurons in all strains. Systemic administration of Ro 60-0175 in adult GAERS produced a clear reduction in absence seizures. Discussion: These findings indicate that 5-HT2CRs regulate thalamic extrasynaptic GABAA inhibition and that their activation reduces tonic inhibitory drive in TC neurons while exerting anti-absence effects in vivo. The lower expression of 5-HT2CRs in the GAERS VB suggests altered serotonergic control of thalamic inhibition in absence epilepsy. By reducing tonic GABAergic currents, 5-HT2CR activation may rebalance thalamocortical activity and suppress pathological oscillations, supporting these receptors as potential therapeutic targets for CAE.