Studying the Molecular Determinants of GABAA Receptors Current Desensitization in Human and Experimental Epilepsies
Abstract number :
1.029
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2021
Submission ID :
1826419
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:54 AM
Authors :
Gabriele Ruffolo, MD, PhD - Sapienza University of Rome; Pierangelo Cifelli - University of L'Aquila; Michele Guescini - University of Urbino "Carlo Bo"; Elena Barbieri - University of Urbino "Carlo Bo"; Silvia Di Angelantonio - University of Rome "Sapienza"; Veronica Alfano - University of Rome "Sapienza"; Eleonora Aronica - Amsterdam UMC; Eleonora Palma - University of Rome "Sapienza"
Rationale: GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). A use-dependent desensitization following a repetitive GABA stimulation (i.e. rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Past studies have linked GABA current rundown with an altered phosphorylation state of GABAARs in epileptic brain, associated with an alteration of GABAAR subunit expression.
Methods: This phenomenon has been studied and characterized mainly using the technique of membrane microtransplantation of human brain tissues in Xenopus oocytes, but confirmed also by electrophysiological studies on brain slices from animal models and epileptic patients.
Results: We investigated the molecular determinants of GABAA current rundown manipulating the receptor stoichiometry and to studying current rundown on different GABAAR configurations. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits, reaching the maximum current decrease when functional α1β2 receptors are expressed, both in transfected HEK cells and in cDNA-injected Xenopus oocytes.
Furthermore, an interesting perspective is to investigate whether this phenomenon is linked to GABAARs synaptic or extrasynaptic localization. To this purpose, in preliminary experiments we obtained synaptic-markers enriched membranes in order to isolate GABA currents evoked from the post-synaptic apparatus and surrounding areas.
Conclusions: The results obtained until now and the ongoing experiments will shed more light on the physiological importance of the mechanism of GABA current rundown and, since GABAARs represent important therapeutic targets in the treatment of human epilepsy, possess also clinical relevance.
Funding: Please list any funding that was received in support of this abstract.: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 952455.
Basic Mechanisms