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The Journal of Neuroscience, October 1, 1999, 19(19):8312-8318

Human Neuronal -Aminobutyric Acid_A Receptors: Coordinated Subunit mRNA Expression and Functional Correlates in Individual Dentate Granule Cells

Amy R. Brooks-Kayal^{1, 2}, Melissa D. Shumate³, Hong Jin¹, Dean D. Lin³, Tatiana Y. Rikhter¹, Kathryn L. Holloway⁴, and Douglas A. Coulter^{1, 2}

¹ Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, ² Departments of Neurology and Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Departments of ³ Physiology, Pharmacology, and Toxicology and ⁴ Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0599

-Aminobutyric acid_A receptors (GABARs) are heteromeric proteins composed of multiple subunits. Numerous subunit subtypes are expressed in individual neurons, which assemble in specific preferred GABAR configurations. Little is known, however, about the coordination of subunit expression within individual neurons or the impact this may have on GABAR function. To investigate this, it is necessary to profile quantitatively the expression of multiple subunit mRNAs within individual cells. In this study, single-cell antisense RNA amplification was used to examine the expression of 14 different GABAR subunit mRNAs simultaneously in individual human dentate granule cells (DGCs) harvested during hippocampectomy for intractable epilepsy. 4, 2, and -mRNA levels were tightly correlated within individual DGCs, indicating that these subunits are expressed coordinately. Levels of 3- and 2-mRNAs, as well as - and 1-mRNAs, also were strongly correlated. No other subunit correlations were identified. Coordinated expression could not be explained by the chromosomal clustering of GABAR genes and was observed in control and epileptic rats as well as in humans, suggesting that it was not species-specific or secondary to epileptogenesis. Benzodiazepine augmentation of GABA-evoked currents also was examined to determine whether levels of subunit mRNA expression correlated with receptor pharmacology. This analysis delineated two distinct cell populations that differed in clonazepam modulation and patterns of -subunit expression. Clonazepam augmentation correlated positively with the relative expression of 1- and 2-mRNAs and negatively with 4- and -mRNAs. These data demonstrate that specific GABAR subunit mRNAs exhibit coordinated control of expression in individual DGCs, which has significant impact on inhibitory function.

Key words: GABA_A receptors; dentate granule cells; hippocampus; human; gene expression; mRNA; patch clamp; zinc; benzodiazepine

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19198312-07$05.00/0

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