GABA(A)-RECEPTOR ALPHA-SUBUNIT IS AN ESSENTIAL PREREQUISITE FOR RECEPTOR FORMATION IN-VIVO

The mechanisms governing the assembly of alpha-, beta- and gamma-subun its to form GABA(A)-receptors are poorly understood. Here, we report t hat the alpha-subunit is essential for receptor assembly. In mice homo zygous for a deletion on chromosome 7 spanning the alpha 5- and gamma 3-subunit genes,(7) zolpidem-insensitive benzodiazepine binding sites, corresponding to GABA(A)-receptors containing the alpha 5-subunit, we re absent in the hippocampus. This loss of alpha 5-GABA(A)-receptor bi nding was also apparent as a 21% decrease in the total number of benzo diazepine binding sites in the hippocampus. In addition, immunoreactiv ity for the beta 2,3- and gamma 2-subunit was decreased exclusively in neurons which normally express the alpha 5-subunit, such as olfactory bulb granule cells and hippocampal pyramidal cells. In other brain re gions of the mutants, the beta 2,3- and gamma 2-subunit staining was u naffected. Controls included two lines of mice homozygous for a shorte r chromosomal deletion, that either included or excluded the gamma 3-s ubunit gene. These two lines were indistinguishable with regard to num bers of benzodiazepine binding sites and levels alpha 5-, beta 2,3- an d gamma 2-subunit immunoreactivity, indicating that the lack of gamma 3-subunit gene did not contribute to the observed deficit in receptor formation. These results demonstrate that the absence of the alpha 5-s ubunit gene prevents the formation of the entire respective receptor c omplex in adult mouse brain. Thus, the alpha-subunit, unlike the gamma 2-subunit, might play a major role in the assembly or targeting of GA BA(A)-receptor complexes. (C) 1997 IBRO. Published by Elsevier Science Ltd.