Turnover and down-regulation of GABA(A) receptor alpha 1, beta 2S, and gamma 1 subunit mRNAs by neurons in culture

Benzodiazepines (BZDs), barbiturates, ethanol, and general anesthetics pote ntiate the action of gamma-aminobutyric acid (GABA) at the type A GABA rece ptor (GABA(A)R) and have profound effects on mood, arousal, and susceptibil ity to seizures. GABA(A)R number and subunit mRNA levels change in animal m odels of epilepsy and anxiety and following exposure to GABA(A)R agonists a nd positive modulators, but the mechanism of receptor down-regulation remai ns unknown. Persistent exposure (48 h) of brain neurons in primary culture to GABA results in a 30% decrease in the levels of mRNA encoding the alpha 1, beta 2S, and gamma 1 GABA(A)R subunit isoforms, which form a receptor en hanced by nonselective BZDs, Down-regulation of alpha 1 mRNA(t1/2 = 8 h) pr ecedes down-regulation of receptor number (t1/2 = 25 h), suggesting that GA BA-induced GABA(A)R down-regulation is a consequence of decreased mRNA leve ls, The apparent half-life of the al mRNA in the presence of alpha-amanitin (9 h) is consistent with the time course of alpha 1 mRNA down-regulation. Moreover, the stability of the alpha 1, beta 2S, and gamma 1 subunit mRNAs is not altered by chronic GABA exposure. The results demonstrate that GABA( A)R subunit mRNA down-regulation is not a consequence of accelerated mRNA d egradation and argue that GABA-induced GABA(A)R down-regulation is due to i nhibition of transcription.