Dystroglycan Is Selectively Associated with Inhibitory GABAergic Synapses but Is Dispensable for Their Differentiation

Sabine Lévi, R. Mark Grady, Michael D. Henry, Kevin P. Campbell, Joshua R. Sanes, Ann Marie Craig

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

The dystrophin glycoprotein complex (DGC) is a multimolecular complex that links the extracellular matrix to the cytoskeleton. The DGC is present at the skeletal neuromuscular junction and required for its maturation and maintenance. Members of the DGC are also expressed in brain. We used cultured hippocampal neurons to analyze the distribution, regulation, and role in synaptogenesis of the major transmembrane component of the DGC, dystroglycan; one of its extracellular ligands, agrin; and one of its cytoskeletal binding partners, dystrophin. α-Dystroglycan, β-dystroglycan, and dystrophin clustered at a subset of inhibitory synapses containing GABAAR subunits α1, α2, and γ2, and the inhibitory receptor anchoring protein gephyrin. DGC components were not detected at excitatory glutamatergic synapses. Dystroglycan is the first identified adhesive macromolecule at mature GABA synapses. Developmentally, dystroglycan clustered at synaptic loci after synaptic vesicles, GABAAR, and gephyrin, the latter being closely associated with GABAAR at all stages of synaptogenesis analyzed. Analysis of gephyrin -/-, agrin -/-, and mdx mouse hippocampal neurons in culture indicated that synaptic clustering of dystroglycan occurs independently of gephyrin, agrin, and dystrophin. In dystroglycan-deficient neurons, cultured from a conditional mutant strain, GABAergic synapses differentiated with clusters of gephyrin and GABAAR apposed to synaptic terminals, but these synapses did not contain detectable dystrophin. Thus the DGC is not essential for GABAergic synaptogenesis but is likely to function in modulating inhibitory synapses or conferring specialized properties on a subset of them.

Original languageEnglish
Pages (from-to)4274-4285
Number of pages12
JournalJournal of Neuroscience
Volume22
Issue number11
StatePublished - Jun 1 2002

Keywords

  • Agrin
  • Dystrophin
  • GABA receptor
  • Gephyrin
  • Mdx
  • Synaptogenesis

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