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The Journal of Neuroscience, June 15, 2002, 22(12):4805-4813

GABAergic Terminals Are Required for Postsynaptic Clustering of Dystrophin But Not of GABA_A Receptors and Gephyrin

Ina Brünig¹, Anthi Suter¹, Irene Knuesel¹, Bernhard Lüscher², and Jean-Marc Fritschy¹

¹ Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland, and ² Department of Biology and Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802

In rat hippocampal cultures, we show by multilabeling immunocytochemistry that pyramidal cells, which receive little or no GABAergic input, mistarget ₂-GABA_A receptors and gephyrin to glutamatergic terminals. This mismatch does not occur in neurons innervated by numerous GABAergic terminals. A similar phenomenon has been reported for isolated autaptic hippocampal neurons (Rao et al., 2000). GABAergic synapses typically form multiple release sites apposed to GABA_A receptor and gephyrin clusters. Remarkably, dystrophin, a protein highly abundant in skeletal muscle membranes, is extensively colocalized with ₂-GABA_A receptors exclusively opposite GABAergic terminals. In addition, selective apposition of syntrophin and -dystroglycan to GABAergic presynaptic terminals suggests that the entire dystrophin-associated protein complex (DPC) clusters at GABAergic synapses. In contrast to gephyrin and GABA_A receptors, DPC proteins are not mistargeted to glutamatergic synapses, indicating independent clustering mechanisms. This was confirmed in hippocampal neurons cultured from GABA_A receptor ₂ subunit-deficient mice. Clustering of GABA_A receptor and gephyrin in these neurons was strongly impaired, whereas clustering of dystrophin and associated proteins was unaffected by the absence of the ₂ subunit. Our results indicate that accumulation of dystrophin and DPC proteins at GABAergic synapses occurs independently of postsynaptic GABA_A receptors and gephyrin. We suggest that selective signaling from GABAergic terminals contributes to postsynaptic clustering of dystrophin.

Key words: GABAergic synapse; dystrophin; dystrophin-associated protein complex; presynaptic signaling; clustering; hippocampus; cell culture; immunofluorescence

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22124805-09$05.00/0

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