Neuroscience New Ligands for Neurexins

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Synapses are complex structures that form between a neuron’s axon and the target cell, and both the presynaptic and postsynaptic cell become specialized and contribute to the formation of the synapse. Many trans-synaptic signals and complexes have been identified that contribute to synapse formation. Following on the identification of leucine-rich repeat transmembrane proteins (LRRTMs) as postsynaptic contributors in an artificial synapse-formation assay (the formation of synapses between nonneuronal cells expressing specific candidate proteins cocultured with neuronal cells), Ko et al. and de Wit et al. found that LRRTM2 contributed to the formation of excitatory synapses and bound neurexin-1 and -1β, which are also known to bind the trans-synaptic protein neuroligin-1. Both groups analyzed the activity of LRRTM2 in the artificial synapse assay and also found an increase in excitatory synapses when LRRTM2 was overexpressed in cultured hippocampal neurons. de Wit et al. also showed that knockdown of LRRTM2 in cultured hippocampal neurons decreased excitatory synapse density without affecting inhibitory synapse density and decreased the abundance of AMPA-type glutamate receptors at the synaptic cell surface. de Wit et al. showed that, when cotransfected into 293T cells, the extracellular LRR domain interacted with both AMPA-type and NMDA-type glutamate receptors and that the intracellular domain interacted with postsynaptic density protein-95 (PSD-95), a scaffolding protein. de Wit et al. confirmed the importance of LRRTM2 in vivo by knocking down the protein in the dentate gyrus of rat pups and observing a specific decrease in both evoked and spontaneous excitatory postsynaptic currents. Both groups also used an affinity purification scheme to identify neurexins-1 and -1β as interacting with the extracellular domain of LRRTM2. Ko et al. further showed that it was the splice variants of the neurexins lacking an insert in splice site #4 that bound LRRTM2, whereas both forms of the neurexins interacted with neuroligin-1. de Wit et al. showed that when neurexin-1 was knocked down in the neurons of the artificial synapse assay, LRRTM2 (expressed in 293T cells) failed to stimulate presynaptic differentiation. Ko et al. showed that soluble neurexin-1β blocked the activity of LRRTM2 in the artificial synapse assay. Thus, neurexins now have two possible partners, LRRTM2 and neuroligin-1, with the interaction with LRRTM2 functioning specifically in excitatory synapse formation

J. Ko, M. V. Fuccillo, R. C. Malenka, T. C. Südhof, LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron 64, 791–798 (2009). [Online Journal]

J. de Wit, E. Sylwestrak, M. L. O’Sullivan, S. Otto, K. Tiglio, J. N. Savas, J. R. Yates III, D. Comoletti, P. Taylor, A. Ghosh, LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 64, 799–806 (2009).[Online Journal]

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