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The Journal of Neuroscience, January 19, 2005, 25(3):594-603; doi:10.1523/JNEUROSCI.4011-04.2005

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Cellular/Molecular
Distinct 2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABA_A Receptors and Gephyrin

Melissa J. Alldred,^1,2 Jonas Mulder-Rosi,^1,2 Sue E. Lingenfelter,^1,2 Gong Chen,¹ and Bernhard Lüscher^1,2

Departments of ¹Biology and ²Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802

Modulation of the concentration of postsynaptic GABA_A receptors contributes to functional plasticity of inhibitory synapses. The 2 subunit of GABA_A receptor is specifically required for clustering of these receptors, for recruitment of the submembrane scaffold protein gephyrin to postsynaptic sites, and for postsynaptic function of GABAergic inhibitory synapses. To elucidate this mechanism, we here have mapped the 2 subunit domains required for restoration of postsynaptic clustering and function of GABA_A receptors in 2 subunit mutant neurons. Transfection of 2^-/- neurons with the 2 subunit but not the 2 subunit rescues postsynaptic clustering of GABA_A receptors, results in recruitment of gephyrin to postsynaptic sites, and restores the amplitude and frequency of miniature inhibitory postsynaptic currents to wild-type levels. Analogous analyses of chimeric 2/2 subunit constructs indicate, unexpectedly, that the fourth transmembrane domain of the 2 subunit is required and sufficient for postsynaptic clustering of GABA_A receptors, whereas cytoplasmic 2 subunit domains are dispensable. In contrast, both the major cytoplasmic loop and the fourth transmembrane domain of the 2 subunit contribute to efficient recruitment of gephyrin to postsynaptic receptor clusters and are essential for restoration of miniature IPSCs. Our study points to a novel mechanism involved in targeting of GABA_A receptors and gephyrin to inhibitory synapses.

Key words: GABAergic; GAD; synapse; synaptogenesis; trafficking; clustering; IPSP; lipid raft; gephyrin; endocytic recycling; IPSC; miniature currents

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Received Sep 28, 2004; revised November 22, 2004; accepted November 26, 2004.

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