Human neuronal gamma-aminobutyric acid(A) receptors: Coordinated subunit mRNA expression and functional correlates in individual dentate granule cells

gamma-Aminobutyric acid(A) receptors (GABARs) are heteromeric proteins comp osed of multiple subunits. Numerous subunit subtypes are expressed in indiv idual neurons, which assemble in specific preferred GABAR configurations. L ittle is known, however, about the coordination of subunit expression withi n individual neurons or the impact this may have on GABAR function. To inve stigate this, it is necessary to profile quantitatively the expression of m ultiple subunit mRNAs within individual cells. In this study, single-cell a ntisense RNA amplification was used to examine the expression of 14 differe nt GABAR subunit mRNAs simultaneously in individual human dentate granule c ells (DGCs) harvested during hippocampectomy for intractable epilepsy. alph a 4, beta 2, and delta-mRNA levels were tightly correlated within individua l DGCs, indicating that these subunits are expressed coordinately. Levels o f alpha 3- and beta 2-mRNAs, as well as epsilon- and beta 1-mRNAs, also wer e strongly correlated. No other subunit correlations were identified. Coord inated expression could not be explained by the chromosomal clustering of G ABAR genes and was observed in control and epileptic rats as well as in hum ans, suggesting that it was not species-specific or secondary to epileptoge nesis. Benzodiazepine augmentation of GABA-evoked currents also was examine d to determine whether levels of subunit mRNA expression correlated with re ceptor pharmacology. This analysis delineated two distinct cell populations that differed in clonazepam modulation and patterns of alpha-subunit expre ssion. Clonazepam augmentation correlated positively with the relative expr ession of alpha 1- and gamma 2-mRNAs and negatively with alpha 4- and delta -mRNAs. These data demonstrate that specific GABAR subunit mRNAs exhibit co ordinated control of expression in individual DGCs, which has significant i mpact on inhibitory function.