Neuroligins, a family of postsynaptic adhesion molecules, are important in synaptogenesis through a well-characterized trans-synaptic interaction with neurexin. In addition, neuroligins are thought to drive postsynaptic assembly through binding of their intracellular domain to PSD-95. However, there is little direct evidence to support the functional necessity of the neuroligin intracellular domain in postsynaptic development. We found that presence of endogenous neuroligin obscured the study of exogenous mutated neuroligin. We therefore used chained microRNAs in rat organotypic hippocampal slices to generate a reduced background of endogenous neuroligin. On this reduced background, we found that neuroligin function was critically dependent on the cytoplasmic tail. However, this function required neither the PDZ ligand nor any other previously described cytoplasmic binding domain, but rather required a previously unknown conserved region. Mutation of a single critical residue in this region inhibited neuroligin-mediated excitatory synaptic potentiation. Finally, we found a functional distinction between neuroligins 1 and 3.
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We thank A.M. Craig, T. Sudhof and F. Varoqueaux for neuroligin constructs. We are grateful to K. Bjorgan for technical assistance and all members of the Nicoll laboratory and E. Dreyfuss for discussion of and comments on the manuscript. This work was supported by grants from the US National Institute of Mental Health.
The authors declare no competing financial interests.
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Shipman, S., Schnell, E., Hirai, T. et al. Functional dependence of neuroligin on a new non-PDZ intracellular domain. Nat Neurosci 14, 718–726 (2011). https://doi.org/10.1038/nn.2825
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