Abstract
Altered expression of GABA receptors (GABAARs) has been implicated in neurological and psychiatric disorders, but limited information about region-specific GABAAR subunit expression in healthy human brains, heteromeric assembly of major isoforms, and their collective organization across healthy individuals, are major roadblocks to understanding their role in non-physiological states. Here, by using microarray and RNA-Seq datasets—from single cell nuclei to global brain expression—from the Allen Institute, we find that transcriptional expression of GABAAR subunits is anatomically organized according to their neurodevelopmental origin. The data show a combination of complementary and mutually-exclusive expression patterns that delineate major isoforms, and which is highly stereotypical across brains from control donors. We summarize the region-specific signature of GABAR subunits per subject and its variability in a control population sample that can be used as a reference for remodeling changes during homeostatic rearrangements of GABAAR subunits after physiological, pharmacological or pathological challenges.
Highlights
Altered expression of Gamma-aminobutyric acid (GABA) receptors (GABAARs) has been implicated in neurological and psychiatric disorders, but limited information about region-specific GABAA receptors (GABAARs) subunit expression in healthy human brains, heteromeric assembly of major isoforms, and their collective organization across healthy individuals, are major roadblocks to understanding their role in non-physiological states
For analysis of gene expression of GABAAR subunits in the whole brain, we selected the most representative probe for each gene (Supplementary Data 1) from the Allen Brain Atlas Microarray Study according to the flowchart in Supplementary Fig. 1
Genes for α2, δ, β3, γ1, α5, and β1 contributed up to 43% of the total expression and genes for α3 and α4 up to 4%. These 11 genes contributed for ≈95% of total mRNA coding for GABAARs in the human brain (Fig. 1a)
Summary
Altered expression of GABA receptors (GABAARs) has been implicated in neurological and psychiatric disorders, but limited information about region-specific GABAAR subunit expression in healthy human brains, heteromeric assembly of major isoforms, and their collective organization across healthy individuals, are major roadblocks to understanding their role in non-physiological states. For the third and fourth analyses, we used the RNA-seq dataset from the Allen Institute cell type study (13,348 single-cell nuclei from the medial temporal gyrus (MTG) of two subjects) to determine the coexpression of subunits according to their major classes (excitatory vs inhibitory) and their cell types (24 excitatory neurons and 45 inhibitory neurons) Together, these analyses provide complementary views of the relationships between GABAAR subunits in control human brains across different layers of complexity. The organizational layout of GABAAR subunits in physiological conditions should help in determining their regional changes and remodeling in pathological conditions, and guide pharmacological strategies that target specific brain regions and functions by modulating GABAARs highly enriched in regions of interest
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