Mutations in neurexins have been identified in genetic studies and animal models as risk factors for autism spectrum disorders (ASDs). Neurexins are presynaptic cell adhesion molecules that are essential for synaptic development. They function through interactions with multifarious postsynaptic ligands, including neuroligins and leucine-rich repeat transmembrane proteins (LRRTMs) that have also been implicated in ASDs. However, little is known about the mechanisms regulating neurexin function and how such mechanisms might be targeted therapeutically.

Peng Zhang and colleagues recently found that attachment of a glycan heparan sulfate (HS) on neurexins regulated synaptic structure and function by altering neurexin-ligand binding affinities¹. Expanding on this work, Zhang and colleagues executed an unbiased screen and a subsequent cell-based ligand binding assay, which successfully identified a specific HS moiety as critical for neurexin-ligand binding.

In the current project, Zhang proposes to assess how enhancements to and blockade of such an HS motif alter neurexin function and synaptic properties. Zhang’s team will leverage these findings to further test whether such modulations alleviate synaptic deficits in an ASD mouse model that harbors a loss-of-function mutation in the neurexin-1 gene (Nrxn1).

Findings from this study will help to determine whether reagents that target HS glycan-binding motifs are a potential therapeutic strategy for restoring pathways disrupted in ASD.