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

Cavaccini, Anna, Venzi, Marcello, Bombardi, Cristiano, Crunelli, Vincenzo ORCID: https://orcid.org/0000-0001-7154-9752 and Di Giovanni, Giuseppe 2026. Thalamic distribution and effects of 5-HT2C receptors on tonic GABAA inhibition and absence seizures: implications for treatment. Frontiers in Pharmacology 17 , 1729460. 10.3389/fphar.2026.1729460

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Abstract

Introduction Childhood absence epilepsy (CAE) is associated with abnormal thalamocortical oscillations and enhanced GABAergic function in the ventrobasal (VB) thalamus, including increased extrasynaptic GABA A receptor–mediated tonic currents in thalamocortical (TC) neurons. Serotonin signaling modulates seizure activity in several epilepsy models, and activation of 5-HT 2C receptors (5-HT 2C Rs) has been reported to exert anti-absence seizure effects, although the underlying cellular mechanisms remain unclear. Here, we examined the thalamic distribution of 5-HT 2C Rs and their functional impact on tonic GABAA inhibition and absence seizures. Methods 5-HT 2C R 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-HT 2C R 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-HT 2C Rs 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-HT 2C Rs 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-HT 2C Rs in the GAERS VB suggests altered serotonergic control of thalamic inhibition in absence epilepsy. By reducing tonic GABAergic currents, 5-HT 2C R activation may rebalance thalamocortical activity and suppress pathological oscillations, supporting these receptors as potential therapeutic targets for CAE.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Start Date: 2026-02-20
Publisher:	Frontiers Media
Date of First Compliant Deposit:	3 March 2026
Last Modified:	03 Mar 2026 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/185401

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