Developmental co-regulation of the beta and gamma GABAA receptor subunits with distinct alpha subunits in the human dorsolateral prefrontal cortex.

摘要

The GABA(A) receptor (GABA(A)R) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2alpha, 2beta and 1gamma subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expression of the beta and gamma subunit mRNAs in the prefrontal cortex would show complementary or opposing patterns of change as compared to the alpha subunits. Certain GABA(A)R 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 3beta and 3gamma 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(A)R genes. beta1, gamma1 and gamma3 subunits decreased in expression with age whereas gamma2 increased. beta2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while beta3 levels remained relatively constant. Using published alpha subunit data we identified two principal components labeled 'Decreasing' (alpha2, alpha5, beta1, gamma1 and gamma3) and 'Dynamic' (alpha1, alpha4, beta2 and gamma2) responsible for 84% of the variation in GABA(A)R 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(A)R subunits could foster better pediatric pharmaceutical treatments.