Heparan sulfate organizes neuronal synapses through neurexin partnerships

• Peng Zhang ^[1] ; Hong Lu ^[1] ; Rui T. Peixoto ^[2]
  1. [1] University of British Columbia

     University of British Columbia

     Canadá

     
  2. [2] Harvard Medical School

     Harvard Medical School

     City of Boston, Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 6, 2018, págs. 1450-1464
• Idioma: inglés
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• Resumen

  • Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin’s role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development.