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

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Abstract
The δ subunit is a novel subunit of the pentameric γ‐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 δ subunit have been produced by gene‐targeting technology, and these mice were studied with immunohistochemical and immunoblot methods to determine whether changes in GABAA receptors were limited to deletion of the δ subunit or whether alterations in other GABAA receptor subunits were also present in the δ subunit knockout (δ–/–) mice. Immunohistochemical studies of wild‐type mice confirmed the restricted distribution of the δ subunit in the forebrain. Regions with moderate to high levels of δ subunit expression included thalamic relay nuclei, caudate‐putamen, molecular layer of the dentate gyrus, and outer layers of the cerebral cortex. Virtually no δ 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 δ–/– and wild‐type mice demonstrated substantial changes in the α4 and γ2 subunits of the GABAA receptor in the δ–/– mice. γ2 Subunit expression was increased, whereas α4 subunit expression was decreased in δ–/– mice. Importantly, alterations of both the α4 and the γ2 subunits were confined primarily to brain regions that normally expressed the δ subunit. This suggests that the additional subunit changes are directly linked to loss of the δ subunit and could reflect local changes in subunit composition and function of GABAA receptors in δ–/– mice. J. Comp. Neurol. 446:179–197, 2002.