eLife (Sep 2020)

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

  • Shinichiro Oku,
  • Huijuan Feng,
  • Steven Connor,
  • Andrea Toledo,
  • Peng Zhang,
  • Yue Zhang,
  • Olivier Thoumine,
  • Chaolin Zhang,
  • Ann Marie Craig

DOI
https://doi.org/10.7554/eLife.58668
Journal volume & issue
Vol. 9

Abstract

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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.

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