Postsynaptic Clustering of γ -Aminobutyric Acid Type A Receptors by the γ 3 Subunit in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-10, Vol.96 (22), p.12860-12865
• Main Authors: Baer, Kristin, Essrich, Christian, Benson, Jack A., Benke, Dietmar, Bluethmann, Horst, Fritschy, Jean-Marc, Lüscher, Bernhard
• Format: Article
• Language: English
• Subjects: Binding sites; Cerebellum; Drug interactions; Genotypes; gephyrin; Hippocampus; Mice; Neurons; Receptors; Transgenes; Transgenic animals
• ISSN: 0027-8424
• DOI: 10.1073/pnas.96.22.12860

Synaptic localization of γ -aminobutyric acid type A (GABAA) receptors is a prerequisite for synaptic inhibitory function, but the mechanism by which different receptor subtypes are localized to postsynaptic sites is poorly understood. The γ 2 subunit and the postsynaptic clustering protein gephyrin are required for synaptic localization and function of major GABAA receptor subtypes. We now show that transgenic overexpression of the γ 3 subunit in γ 2 subunit-deficient mice restores benzodiazepine binding sites, benzodiazepine-modulated whole cell currents, and postsynaptic miniature currents, suggesting the formation of functional, postsynaptic receptors. Moreover, the γ 3 subunit can substitute for γ 2 in the formation of GABAA receptors that are synaptically clustered and colocalized with gephyrin in vivo. These clusters were formed even in brain regions devoid of endogenous γ 3 subunit, indicating that the factors present for clustering of γ 2 subunit-containing receptors are sufficient to cluster γ 3 subunit-containing receptors. The GABAA receptor and gephyrin-clustering properties of the ectopic γ 3 subunit were also observed for the endogenous γ 3 subunit, but only in the absence of the γ 2 subunit, suggesting that the γ 3 subunit is at a competitive disadvantage with the γ 2 subunit for clustering of postsynaptic GABAA receptors in wild-type mice.