Neurexins constitute a family of presynaptic transmembrane molecules that are encoded by three distinct genes, and mutations in all three genes are associated with risk for autism spectrum. In mammals, neurexins are expressed as thousands of different splice isoforms, all containing an invariant intracellular domain responsible for an as yet uncharacterized downstream signaling pathway. In the current project, Peri Kurshan and colleagues plan to use the simpler in vivo system afforded by the nematode C. elegans, along with a recently developed proteomics approach, to identify the proteins responsible for neurexin’s downstream signaling pathway(s).