Investigation of the abundance and subunit composition of GABA(A) receptor subtypes in the cerebellum of alpha 1-subunit-deficient mice

In cerebellum, 75% of all GABA(A) receptors contain alpha 1 subunits. Here, we investigated compensatory changes in GABA(A) receptor subunit expression and composition in alpha 1 subunit-knockout mice. In these mice the total number of cerebellar GABA(A) receptors was reduced by 46%. Whereas the number of receptors containing alpha 6 subunits was unchanged, the total amount of alpha 6 subunits was significantly elevated. RT-PCR showed no increase of alpha 6 mRNA levels, arguing against increased biosynthesis of these subunits. Elevated levels of alpha 6 subunits in alpha 1 -/- mice might thus have been caused by an increased incorporation of unassembled alpha 6 subunits, replacing alpha 1 subunits in alpha 1 alpha 6 beta gamma 2 or alpha 1 alpha 6 beta delta receptors, thus rescuing alpha 6 subunits from degradation. Elevated levels of alpha 3 and alpha 4 subunits in the cerebellum of alpha 1 -/- mice possibly can be explained similarly. Finally, a small amount of receptors containing no gamma or delta subunits was identified in these mice. Results suggest a total loss of GABA(A) receptors in cell types where alpha 1 was the only alpha subunit expressed and a partial compensation for receptor loss in cell types containing other alpha subunits. Our results do not support a significant compensatory synthesis of other GABA(A) receptor subunits in the cerebellum of alpha 1 -/- mice.