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

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.