Compensatory alteration of inhibitory synaptic circuits in cerebellum and thalamus of γ‐aminobutyric acid type A receptor α1 subunit knockout mice

作者：Jason E. Kralic, Corinne Sidler, Franziska Parpan, Gregg E. Homanics, A. Leslie Morrow, Jean‐Marc Fritschy · 发表于：The Journal of Comparative Neurology · 年份：2006 · DOI：10.1002/cne.20866 · 被引用次数：136 · 研究领域：Neuroscience and Neuropharmacology Research、Nicotinic Acetylcholine Receptors Study、Ion channel regulation and function

Targeted deletion of the alpha1 subunit gene results in a profound loss of gamma-aminobutyric acid type A (GABA(A)) receptors in adult mouse brain but has only moderate behavioral consequences. Mutant mice exhibit several adaptations in GABA(A) receptor subunit expression, as measured by Western blotting. By using immunohistochemistry, we investigated here whether these adaptations serve to replace the missing alpha1 subunit or represent compensatory changes in neurons that normally express these subunits. We focused on cerebellum and thalamus and distinguished postsynaptic GABA(A) receptor clusters by their colocalization with gephyrin. In the molecular layer of the cerebellum, alpha1 subunit clusters colocalized with gephyrin disappeared from Purkinje cell dendrites of mutant mice, whereas alpha3 subunit/gephyrin clusters, presumably located on dendrites of Golgi interneurons, increased sevenfold, suggesting profound network reorganization in the absence of the alpha1 subunit. In thalamus, a prominent increase in alpha3 and alpha4 subunit immunoreactivity was evident, but without change in regional distribution. In the ventrobasal complex, which contains primarily postsynaptic alpha1- and extrasynaptic alpha4-GABA(A) receptors, the loss of alpha1 subunit was accompanied by disruption of gamma2 subunit and gephyrin clustering, in spite of the increased alpha4 subunit expression. However, in the reticular nucleus, which lacks alpha1-GABA(A) receptors in wild-type mice, postsy...