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The Journal of Neuroscience, November 1, 1999, 19(21):9289-9297

Loss of Postsynaptic GABA_A Receptor Clustering in Gephyrin-Deficient Mice

Matthias Kneussel¹, Johann Helmut Brandstätter², Bodo Laube¹, Sabine Stahl¹, Ulrike Müller¹, and Heinrich Betz¹

Departments of ¹ Neurochemistry and ² Neuroanatomy, Max-Planck-Institute for Brain Research, D-60528 Frankfurt/Main, Germany

The tubulin-binding protein gephyrin, which anchors the inhibitory glycine receptor (GlyR) at postsynaptic sites, decorates GABAergic postsynaptic membranes in various brain regions, and postsynaptic gephyrin clusters are absent from cortical cultures of mice deficient for the GABA_A receptor 2 subunit. Here, we investigated the postsynaptic clustering of GABA_A receptors in gephyrin knock-out (geph /) mice. Both in brain sections and cultured hippocampal neurons derived from geph / mice, synaptic GABA_A receptor clusters containing either the 2 or the 2 subunit were absent, whereas glutamate receptor subunits were normally localized at postsynaptic sites. Western blot analysis and electrophysiological recording revealed that normal levels of functional GABA_A receptors are expressed in geph / neurons, however the pool size of intracellular GABA_A receptors appeared increased in the mutant cells. Thus, gephyrin is required for the synaptic localization of GlyRs and GABA_A receptors containing the 2 and/or 2 subunits but not for the targeting of these receptors to the neuronal plasma membrane. In addition, gephyrin may be important for efficient membrane insertion and/or metabolic stabilization of inhibitory receptors at developing postsynaptic sites.

Key words: GABA_A receptor; gephyrin; receptor clustering; knock-out mice; hippocampal cultures; NMDA receptor; AMPA receptor; PSD-95

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19219289-09$05.00/0

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