Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity

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...

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Bibliographic Details
Published in:eLife 2020-09, Vol.9
Main Authors: Oku, Shinichiro, Feng, Huijuan, Connor, Steven, Toledo, Andrea, Zhang, Peng, Zhang, Yue, Thoumine, Olivier, Zhang, Chaolin, Craig, Ann Marie
Format: Article
Language:English
Subjects:
Alternative Splicing
Animal biology
Animals
Autism
Cell Adhesion Molecules, Neuronal - metabolism
Developmental Biology
Female
GABA
Life Sciences
Male
Mice
Mice, Knockout
neuroligin
Neurons
Neuroscience
Polysaccharides - metabolism
Rats
Synapses - physiology
synaptic adhesion protein
synaptogenesis
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Summary: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 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.58668