GABAA receptor changes in δ subunit-deficient mice:: Altered expression of α4 and γ2 subunits in the forebrain

The 6 subunit is a novel subunit of the pentameric gamma-aminobutyric acid (GABA)A receptor that conveys special pharmacological and functional properties to recombinant receptors and may be particularly important in mediating tonic inhibition. Mice that lack the 8 subunit have been produced by gene-targeting technology, and these mice were studied with immunohistochemical and immunoblot methods to determine whether changes in GABA(A) receptors were limited to deletion of the 8 subunit or whether alterations in other GABA(A) receptor subunits were also present in the 8 subunit knockout (delta-/-) mice. Immunohistochemical studies of wild-type mice confirmed the restricted distribution of the 8 subunit in the forebrain. Regions with moderate to high levels of 6 subunit expression included thalamic relay nuclei, caudate-putamen, molecular layer of the dentate gyrus, and outer layers of the cerebral cortex. Virtually no 8 subunit labeling was evident in adjacent regions, such as the thalamic reticular nucleus, hypothalamus, and globus pallidus. Comparisons of the expression of other subunits in delta-/- and wild-type mice demonstrated substantial changes in the alpha4 and gamma2 subunits of the GABA(A) receptor in the delta-/- mice. gamma2 Subunit expression was increased, whereas alpha4 subunit expression was decreased in delta-/- mice. Importantly, alterations of both the a4 and the gamma2 subunits were confined primarily to brain regions that normally expressed the 8 subunit. This suggests that the additional subunit changes are directly linked to loss of the 8 subunit and could reflect local changes in subunit composition and function of GABAA receptors in delta-/- mice. (C) 2002 Wiley-Liss, Inc.