MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin

Neuron. 2015 Jun 17;86(6):1420-32. doi: 10.1016/j.neuron.2015.05.015. Epub 2015 May 28.


At synapses, the presynaptic release machinery is precisely juxtaposed to the postsynaptic neurotransmitter receptors. We studied the molecular mechanisms underlying this exquisite alignment at the C. elegans inhibitory synapses. We found that the sole C. elegans neuroligin homolog, NLG-1, localizes specifically at GABAergic postsynapses and is required for clustering the GABA(A) receptor UNC-49. Two presynaptic factors, Punctin/MADD-4, an ADAMTS-like extracellular protein, and neurexin/NRX-1, act partially redundantly to recruit NLG-1 to synapses. In the absence of both MADD-4 and NRX-1, NLG-1 and GABA(A) receptors fail to cluster, and GABAergic synaptic transmission is severely compromised. Biochemically, we detect an interaction between MADD-4 and NLG-1, as well as between MADD-4 and NRX-1. Interestingly, the presence of NRX-1 potentiates binding between Punctin/MADD-4 and NLG-1, suggestive of a tripartite receptor ligand complex. We propose that presynaptic terminals induce postsynaptic receptor clustering through the action of both secreted ECM proteins and trans-synaptic adhesion complexes.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • GABAergic Neurons / physiology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Potentials / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Patch-Clamp Techniques
  • Presynaptic Terminals / physiology*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Synaptic Transmission / genetics
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Caenorhabditis elegans Proteins
  • Cell Adhesion Molecules, Neuronal
  • Luminescent Proteins
  • MADD-4 protein, C elegans
  • Nerve Tissue Proteins
  • Receptors, GABA-A
  • Transforming Growth Factor beta
  • UNC-129 protein, C elegans
  • neuroligin 1
  • nrx-1 protein, C elegans