Developmental co-regulation of the beta and gamma GABA(A) receptor subunits with distinct alpha subunits in the human dorsolateral prefrontal cortex

作者：Fillman Stu G; Duncan Carlotta E; Webster Maree J; Elashoff Michael; Weickert Cynthia Shannon^*

来源：International Journal of Developmental Neuroscience, 2010, 28(6): 513-519.

DOI：10.1016/j.ijdevneu.2010.05.004

• Cortical development
• GABAA receptor
• GABAA beta subunit
• GABAA gamma subunit
• GABAA gene expression

The GABA(A) receptor (GABA(A)R) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2 alpha, 2 beta and 1 gamma 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 a 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 3 beta and 3 gamma 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.
beta 1, gamma 1 and gamma 3 subunits decreased in expression with age whereas gamma 2 increased. beta 2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while beta 3 levels remained relatively constant. Using published alpha subunit data we identified two principal components labeled 'Decreasing' (alpha 2, alpha 5, beta 1, gamma 1 and gamma 3) and 'Dynamic' (alpha 1, alpha 4, beta 2 and gamma 2) 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.

• 出版日期2010-10