C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains

Two presynaptically secreted isoforms of the protein Punctin in the nematode Caenorhabditis elegans determine the postsynaptic accumulation of acetylcholine versus GABA receptors, raising the question of whether the related human punctin-2 gene, which has been associated with schizophrenia, may also control synaptic organization. Punctin is a synaptic organizer in C. elegans Most neurons receive myriads of inputs from excitatory and inhibitory neurons, and each presynaptic neurotransmitter must find the appropriate receptor on the facing, postsynaptic surface. Jean-Louis Bessereau and colleagues show that two presynaptically secreted isoforms of the protein Punctin determine the postsynaptic accumulation of acetylcholine versus GABA receptors in the nematode Caenorhabditis elegans . Whether the related human punctin-2 gene, which has been associated with schizophrenia, is also involved in the control of synaptic organization remains to be investigated. Because most neurons receive thousands of synaptic inputs, the neuronal membrane is a mosaic of specialized microdomains where neurotransmitter receptors cluster in register with the corresponding presynaptic neurotransmitter release sites. In many cases the coordinated differentiation of presynaptic and postsynaptic domains implicates trans-synaptic interactions between membrane-associated proteins such as neurexins and neuroligins 1 , 2 , 3 . The Caenorhabditis elegans neuromuscular junction (NMJ) provides a genetically tractable system in which to analyse the segregation of neurotransmitter receptors, because muscle cells receive excitatory innervation from cholinergic neurons and inhibitory innervation from GABAergic neurons 4 . Here we show that Ce-Punctin / madd-4 (ref. 5 ), the C. elegans orthologue of mammalian punctin-1 and punctin-2 , encodes neurally secreted isoforms that specify the excitatory or inhibitory identity of postsynaptic NMJ domains. These proteins belong to the ADAMTS (a disintegrin and metalloprotease with thrombospondin repeats)-like family, a class of extracellular matrix proteins related to the ADAM proteases but devoid of proteolytic activity 6 . Ce-Punctin deletion causes the redistribution of synaptic acetylcholine and GABA A (γ-aminobutyric acid type A) receptors into extrasynaptic clusters, whereas neuronal presynaptic boutons remain unaltered. Alternative promoters generate different Ce-Punctin isoforms with distinct functions. A short isoform is expressed by cholinergic an