Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures

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.