Developmental co-regulation of the β and γ GABA_A receptor subunits with distinct α subunits in the human dorsolateral prefrontal cortex

The GABA_A receptor (GABA_AR) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2α, 2β and 1γ subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expression of the β and γ subunit mRNAs in the prefrontal cortex would show complementary or opposing patterns of change as compared to the α subunits. Certain GABA_AR subunit genes are arranged in tandem on the chromosome, and we hypothesized that genomic proximity would lead to co-regulation during development.The mRNA expression of the 3β and 3γ subunits was measured in the human dorsolateral prefrontal cortex of 68 individuals aged neonate to adult, using microarray with qPCR validation. Changes between age groups were identified through ANOVA, linear regression and post hoc Fisher LSD tests while a principal component analysis was used to establish co-regulation of GABA_AR genes.β1, γ1 and γ3 subunits decreased in expression with age whereas γ2 increased β2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while β3 levels remained relatively constant. Using published α subunit data we identified two principal components labeled 'Decreasing' (α2, α5, β1, γ1 and γ3) and 'Dynamic' (α1, α4, β2 and γ2) responsible for 84% of the variation in GABA_AR subunit development.This grouping is generally consistent with the chromosomal localization of subunits, lending credence to regional transcriptional control mechanisms. In addition, understanding developmental changes in GABA_AR subunits could foster better pediatric pharmaceutical treatments.