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Compensatory alteration of inhibitory synaptic circuits in cerebellum and thalamus of γ‐aminobutyric acid type A receptor α1 subunit knockout mice
Author(s) -
Kralic Jason E.,
Sidler Corinne,
Parpan Franziska,
Homanics Gregg E.,
Morrow A. Leslie,
Fritschy JeanMarc
Publication year - 2006
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/cne.20866
Subject(s) - gephyrin , biology , postsynaptic potential , protein subunit , gabaergic , cerebellum , neuroscience , inhibitory postsynaptic potential , thalamic reticular nucleus , microbiology and biotechnology , glycine receptor , receptor , biochemistry , amino acid , gene , glycine
Targeted deletion of the α1 subunit gene results in a profound loss of γ‐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 α1 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, α1 subunit clusters colocalized with gephyrin disappeared from Purkinje cell dendrites of mutant mice, whereas α3 subunit/gephyrin clusters, presumably located on dendrites of Golgi interneurons, increased sevenfold, suggesting profound network reorganization in the absence of the α1 subunit. In thalamus, a prominent increase in α3 and α4 subunit immunoreactivity was evident, but without change in regional distribution. In the ventrobasal complex, which contains primarily postsynaptic α1‐ and extrasynaptic α4‐GABA A receptors, the loss of α1 subunit was accompanied by disruption of γ2 subunit and gephyrin clustering, in spite of the increased α4 subunit expression. However, in the reticular nucleus, which lacks α1‐GABA A receptors in wild‐type mice, postsynaptic α3/γ2/gephyrin clusters were unaffected. These results demonstrate that adaptive responses in the brain of α1 0/0 mice involve reorganization of GABAergic circuits and not merely replacement of the missing α1 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. J. Comp. Neurol. 495:408–421, 2006. © 2006 Wiley‐Liss, Inc.