In vivo regulation of specific GABAA receptor subunit messenger RNAs by increased GABA concentrations in rat brain.

This study has examined whether changes in endogenous GABA concentrations influence GABAA receptor subunit mRNA expression in vivo. Increased GABA concentrations were achieved by treating female rats with gamma-vinyl-GABA (15 mg/100 g), an irreversible inhibitor of the GABA transaminase, daily for three days. High performance liquid chromatography analysis of brain punches from specific brain regions showed that gamma-vinyl-GABA treatment resulted in approximately two-fold increases in brain GABA content. Using in situ hybridization techniques with specific 35S-labelled oligonucleotides, the mRNA expression of the alpha 1, alpha 2, beta 2, beta 3, gamma 1 and/or gamma 2 subunits of the GABAA receptor was quantified in various brain regions including the medial preoptic nucleus, bed nucleus of the stria terminalis, bed nucleus of the anterior commissure, supraoptic and paraventricular nuclei of the hypothalamus, globus pallidus and cingulate cortex. Silver grain density analysis showed that gamma-vinyl-GABA treatment induced a significant 35 and 49% decrease in gamma 1 mRNA expression in the medial preoptic nucleus and the principle encapsulated nucleus of the bed nucleus of the stria terminalis respectively, and a significant 20% decrease in alpha 2 mRNA expression in the cingulate cortex. Expression of alpha 2 and beta 3 in the former areas was unchanged as was alpha 1, beta 2, beta 3 and gamma 2 subunit expression in the cingulate cortex. Elevation of brain GABA levels also resulted in a specific and significant 17% increase in gamma 2 mRNA expression in the supraoptic nucleus. In the globus pallidus, gamma-vinyl-GABA treatment induced a significant 29% increase in alpha 1 mRNA expression combined with 19 and 30% decreases in beta 2 and gamma 2 mRNA expression, respectively. Levels of GABAA receptor subunits expressed in the bed nucleus of the anterior commissure (alpha 2, beta 3, gamma 1) and paraventricular nucleus (alpha 1, alpha 2, beta 2, gamma 2) were not changed by gamma-vinyl-GABA treatment. These results provide in vivo evidence for a region- and subunit-specific regulation of GABAA receptor subunit mRNA levels following the elevation of brain GABA concentrations and suggest that endogenous GABA levels influence GABAA receptor subunit mRNA expression.