GABAA receptor subunits in human oligodendrocyte progenitor cells

GABAA receptors (GABAARs) in oligodendrocyte progenitor cells (OPCs) are thought to be an important target for the treatment of demyelinating diseases. In general, GABAARs are pentameric complexes built from 3 different subunits encoded from a pool of 19 genes (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3), still, the subunit combination/s of the receptors in human OPCs remains unknown, delaying their study as potential therapeutic targets. Our aims in the present study were to identify the subunits expressed in GABAARs in human OPCs and to predict their stoichiometry. For the expression analysis, we used 8 available transcriptomic datasets from human cerebral cortex of adults without known neurological disorders. We identified OPCs in the sequencing data by selecting cells positive to PDGFRα, an OPC cell surface marker. We normalized the expression units (UMIs) of each dataset by obtaining the fractional contribution (FC) of subunits to the total pool of mRNA available, where FC is the percentage of the sum of the expression levels of each subunit gene in each cell over the sum of all 19 gene subunits. We then evaluated the most likely stoichiometry of the GABAAR in human OPCs by performing a multiple correlation analysis of the FC data using JMP software. We found mRNA expression of most GABAAR subunit genes among all analyzed OPCs. The most abundant subunits were α1–3, β1–3 and γ1–3, while all others were barely detected. In our multivariate analysis, knowing that most GABAARs in other cells are heteropentameric complexes formed by 2αs, 2βs, and 1γ subunit, we looked at the correlations formed by those subunits, finding α1β2γ2, α2β1/2γ2/3, and α3β3γ1 as the best combinations in the indicated order. To the best of our knowledge, this is the first report to identify GABAAR subunits in human OPCs, as well as their likely stoichiometry. Our next goal is to characterize functionally and pharmacologically these receptor subunit combinations in native GABAARs isolated from human OPCs.