Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures
- 1University of Malta
Abstract
Absence epilepsy is a generalized non-convulsive epilepsy characterized by recurrent absence seizures (ASs) and enhanced GABAA receptor-mediated tonic inhibition of thalamocortical (TC) neurons has been shown to lead to ASs. Serotonergic signalling is an important modulator of these seizures, yet the contribution of specific 5-HT receptor subtypes remains incompletely understood. Here, we investigated whether endogenous serotonergic signalling through 5-HT2A receptors (5-HT2ARs) contributes to pathological tonic inhibition and ASs expression. Patch-clamp recordings were obtained from ventrobasal (VB) TC neurons of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control (NEC) rats. The selective 5-HT2AR antagonist MDL11,939 had no effect on tonic GABA-A currents in NEC TC neurons but significantly reduced the enhanced tonic current in GAERS neurons, revealing a disease-dependent contribution of endogenous 5-HT2AR signalling. MDL11,939 administered bilaterally into the VB of freely moving GAERS by reverse microdialysis did not alter ASs. This dissociation between the modulation of a disease-associated cellular mechanism and seizure outcome suggests that the previously reported reduction of ASs by systemic 5-HT2AR blockade may involve mechanisms outside the VB.
Related
- Biphasic Modulation of Absence Seizures by Lisuride in GAERS: Dissecting the Role of 5-HT2A Receptors
- Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures
- PP2A-dependent downregulation of GABAB receptors modulates somatostatin interneurons function and plasticity
- Melatonin modulates habituation learning via the convergent action of two MT1-type receptors.
- WNK-dependent phosphorylation of gephyrin tunes GABA A receptors at inhibitory synapses and modulates anxiety behavior
BibTeX
@misc{cavaccini2026block,
title = {{Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures}},
author = {A. Cavaccini and M. Venzi and V. Crunelli and G. Di Giovanni},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.751734},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.751734v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures
AU - A. Cavaccini
AU - M. Venzi
AU - V. Crunelli
AU - G. Di Giovanni
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.751734
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.751734v1
AB - Absence epilepsy is a generalized non-convulsive epilepsy characterized by recurrent absence seizures (ASs) and enhanced GABAA receptor-mediated tonic inhibition of thalamocortical (TC) neurons has been shown to lead to ASs. Serotonergic signalling is an important modulator of these seizures, yet the contribution of specific 5-HT receptor subtypes remains incompletely understood. Here, we investigated whether endogenous serotonergic signalling through 5-HT2A receptors (5-HT2ARs) contributes to pathological tonic inhibition and ASs expression. Patch-clamp recordings were obtained from ventrobasal (VB) TC neurons of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control (NEC) rats. The selective 5-HT2AR antagonist MDL11,939 had no effect on tonic GABA-A currents in NEC TC neurons but significantly reduced the enhanced tonic current in GAERS neurons, revealing a disease-dependent contribution of endogenous 5-HT2AR signalling. MDL11,939 administered bilaterally into the VB of freely moving GAERS by reverse microdialysis did not alter ASs. This dissociation between the modulation of a disease-associated cellular mechanism and seizure outcome suggests that the previously reported reduction of ASs by systemic 5-HT2AR blockade may involve mechanisms outside the VB.
ER -