Neural connections require precise organization of the presynaptic and postsynaptic neurons. Neuroligins are transmembrane proteins expressed on the postsynaptic cell that bind to β-neurexins, which are presynaptic transmembrane proteins. Graf et al. report that β-neurexin is present in both excitatory (glutamatergic) and inhibitory (GABAergic) presynaptic neurons of the hippocampus. When these cells were plated with COS cells transfected to express neuroligin-1 or neuroligin-2, the presynaptic specializations that contained synaptic vesicles were induced in both types of axons. Coculture of fibroblasts expressing neurexin-1β with hippocampal neurons triggered the formation of PSD-95-positive or gephyrin-positive postsynaptic clusters in contacting dendrites (PSD-95 is an excitatory postsynaptic organizing protein and gephyrin is an inhibitory postsynaptic organizing protein). In addition, neurexin-1β stimulated clustering of N-methyl-D-aspartate (NMDA)-type glutamate receptor subunits and of GABAA receptor subunits. Analysis of the localization of neuroligin-1 (which is limited to excitatory postsynaptic membranes) and neuroligin-2, both of which bind neurexin, indicated that the majority of the gephyrin-positive clusters (inhibitory postsynaptic regions) were neuroligin-2 positive and that only about half of the PSD-95-positive clusters were also associated with neuroligin-2. To verify that clustering of neuroligins was the only requirement for the formation of postsynaptic specializations, neuroligin-1, -2, -3, or -4 was labeled with yellow fluorescent protein (YFP) and clustered using antibody against YFP. Neuroligin-1, -3, or -4 clustering produced PSD-95-positive structures, whereas neuroligin-2 clustering produced PSD-95- and gephyrin-positive structures. Thus, neuroligin isoform specificity contributes to the formation of excitatory or inhibitory postsynaptic structures.
E. R. Graf, X. Zhang, S.-X. Jin, M. W. Linhoff, A. M. Craig, Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119, 1013-1026 (2004). [PubMed]