TY - JOUR TI - Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity AU - Oku, Shinichiro AU - Feng, Huijuan AU - Connor, Steven AU - Toledo, Andrea AU - Zhang, Peng AU - Zhang, Yue AU - Thoumine, Olivier AU - Zhang, Chaolin AU - Craig, Ann Marie A2 - Kennedy, Mary B A2 - Bronner, Marianne E A2 - Kennedy, Mary B VL - 9 PY - 2020 DA - 2020/09/11 SP - e58668 C1 - eLife 2020;9:e58668 DO - 10.7554/eLife.58668 UR - https://doi.org/10.7554/eLife.58668 AB - Post-transcriptional mechanisms regulating cell surface synaptic organizing complexes that control the properties of connections in brain circuits are poorly understood. Alternative splicing regulates the prototypical synaptic organizing complex, neuroligin-neurexin. In contrast to the well-studied neuroligin splice site B, little is known about splice site A. We discovered that inclusion of the positively charged A1 insert in mouse neuroligin-1 increases its binding to heparan sulphate, a modification on neurexin. The A1 insert increases neurexin recruitment, presynaptic differentiation, and synaptic transmission mediated by neuroligin-1. We propose that the A1 insert could be a target for alleviating the consequences of deleterious NLGN1/3 mutations, supported by assays with the autism-linked neuroligin-1-P89L mutant. An enrichment of neuroligin-1 A1 in GABAergic neuron types suggests a role in synchrony of cortical circuits. Altogether, these data reveal an unusual mode by which neuroligin splicing controls synapse development through protein-glycan interaction and identify it as a potential therapeutic target. KW - synaptogenesis KW - synaptic adhesion protein KW - neuroligin KW - alternative splicing KW - autism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -