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CHARACTERISATION OF <EM>GABRD</EM> GAIN OF FUNCTION VARIANTS USING HUMAN STEM CELL-DERIVED GABAERGIC NEURONS
Jonas Laugård Haldand 4 co-authors
University of Copenhagen
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS01-07AM-026
Presentation
Date TBA
Board: PS01-07AM-026
Event Information
Poster Board
PS01-07AM-026
Poster
View posterAbstract
Purpose: While more and more patients with GABAAR variants are being discovered and more variants are characterised using oocyte or HEK cell models, there has yet to be any electrophysiological characterization of a GABAAR variant in human, stem cell-derived neurons. This is a crucial missing translational link for tying functional assays to clinical findings. This project aims to fill that gap.
Method: Stem cell lines were created with variants GABRD L260V and GABRD T291I, as well as isogenic control lines (WT). The lines were differentiated into induced GABAergic neurons by transduction with the genes ASCL1 and DLX2. The cells were grown for 40-45 days, in an autaptic culture system using “islands” of primary mouse glia. Finally, the cells were analysed using whole-cell patch clamp and immunocytochemistry.
Results: The L260V line responded with a significantly larger current amplitude to 1, 3.33, and 10 µM of GABA, with T291I showing significance for 1 and 3.33 µM of GABA. No significant change was found for amplitude or total charge of single evoked inhibitory postsynaptic currents.
Conclusion: Human stem cell-derived GABAergic neurons with the GABRD L260V or T291I variant display a gain of function response to GABA when compared to an isogenic control. This is an important finding, further proving the existence of GABAAR gain of function epilepsies and their clinical implications.
Method: Stem cell lines were created with variants GABRD L260V and GABRD T291I, as well as isogenic control lines (WT). The lines were differentiated into induced GABAergic neurons by transduction with the genes ASCL1 and DLX2. The cells were grown for 40-45 days, in an autaptic culture system using “islands” of primary mouse glia. Finally, the cells were analysed using whole-cell patch clamp and immunocytochemistry.
Results: The L260V line responded with a significantly larger current amplitude to 1, 3.33, and 10 µM of GABA, with T291I showing significance for 1 and 3.33 µM of GABA. No significant change was found for amplitude or total charge of single evoked inhibitory postsynaptic currents.
Conclusion: Human stem cell-derived GABAergic neurons with the GABRD L260V or T291I variant display a gain of function response to GABA when compared to an isogenic control. This is an important finding, further proving the existence of GABAAR gain of function epilepsies and their clinical implications.
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