Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development

J Cell Biol. 2013 Feb 4;200(3):321-36. doi: 10.1083/jcb.201206028. Epub 2013 Jan 28.


Rare variants in MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse-organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin-neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / metabolism*
  • COS Cells
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Chlorocebus aethiops
  • Dendrites / metabolism
  • GPI-Linked Proteins
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Biological
  • Nerve Tissue Proteins / metabolism*
  • Neural Cell Adhesion Molecules / chemistry
  • Neural Cell Adhesion Molecules / metabolism*
  • Neural Inhibition*
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Recombinant Proteins
  • Synapses / metabolism*


  • Cell Adhesion Molecules, Neuronal
  • GPI-Linked Proteins
  • MDGA1 protein, rat
  • MDGA2 protein, mouse
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • Recombinant Proteins
  • neuroligin 1
  • neuroligin 2
  • neurexin Ibeta