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

Targeted deletion of the alpha 1 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 alpha 1 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, alpha 1 subunit clusters colocalized with gephyrin disappeared from Purkinje cell dendrites of mutant mice, whereas alpha 3 subunit/gephyrin clusters, presumably located on dendrites of Golgi interneurons, increased sevenfold, suggesting profound network reorganization in the absence of the alpha 1 subunit. In thalamus, a prominent increase in alpha 3 and alpha 4 subunit immunoreactivity was evident, but without change in regional distribution. In the ventrobasal complex, which contains primarily postsynaptic alpha 1- and extrasynaptic alpha 4-GABA(A) receptors, the loss of alpha 1 subunit was accompanied by disruption of gamma 2 subunit and gephyrin clustering, in spite of the increased a4 subunit expression. However, in the reticular nucleus, which lacks alpha 1-GABA(A) receptors in wild-type mice, postsynaptic alpha 3/gamma 2/gephyrin clusters were unaffected. These results demonstrate that adaptive responses in the brain of alpha 1(0/0) mice involve reorganization of GABAergic circuits and not merely replacement of the missing alpha 1 subunit by another receptor subtype. In addition, clustering of gephyrin at synaptic sites in cerebellum and thalamus appears to be dependent on expression of a GABA(A) receptor subtype localized postsynaptically.