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Presynaptic GABA<jats:sub>B<\/jats:sub>-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABA<jats:sub>B<\/jats:sub>-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABA<jats:sub>B<\/jats:sub>-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABA<jats:sub>B<\/jats:sub>-receptor activation. Moreover, deletion of neurexins caused a loss of GABA<jats:sub>B<\/jats:sub>-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABA<jats:sub>B<\/jats:sub>-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.<\/jats:p>","DOI":"10.1038\/s41467-021-22753-5","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T10:16:55Z","timestamp":1619086615000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Neurexins regulate presynaptic GABAB-receptors at central synapses"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-6545","authenticated-orcid":false,"given":"Fujun","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9313-4176","authenticated-orcid":false,"given":"Alessandra","family":"Sclip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Merrill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-9275","authenticated-orcid":false,"given":"Thomas C.","family":"S\u00fcdhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"22753_CR1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.neuron.2012.06.012","volume":"75","author":"TC Sudhof","year":"2012","unstructured":"Sudhof, T. 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