Genetic data implicate two pathways most strongly in autism spectrum disorders (ASDs): synaptic networks and transcriptional regulatory pathways. NRXN1, encoding the synaptic organizing protein neurexin-1, is a high-risk gene for ASD, accounting for an estimated 0.32% of cases. It is central to the synaptic pathway and binds directly to multiple other ASD risk gene products, suggesting it is a pivotal player in signaling pathways linked to ASD. However, little is known about the mechanisms regulating neurexin function and how such mechanisms might be targeted therapeutically.
Ann Marie Craig and colleagues recently found that neurexins are modified by addition of a rare glycan, heparan sulfate1. Heparan sulfate structure is controlled by cell-type specific modifying enzymes, thus contributing to neurexin diversity. Functionally, heparan sulfate modification controls binding of neurexins to known postsynaptic ligands, including neuroligins and leucine-rich repeat transmembrane proteins (LRRTMs), as well as to novel ligands, thus impacting synaptogenesis and neurotransmission.
Craig’s team will leverage these recent findings to test a new direction for restoring synaptic pathways in ASD. The hypothesis is that synaptic deficits resulting from an ASD-associated loss-of-function mutation in one NRXN1 allele will be alleviated by modulating the remaining NRXN1 allele to boost neurexin-1 function. The hypothesis will be tested by analyses of novel mouse models for synaptic structure and function using imaging and electrophysiological approaches. The focus will be on hippocampal synapses where neurexin-1 is known to be required, with extension to the prefrontal cortex. Co-investigator Richard Brown (Dalhousie University) will assess genotype, age and sex differences across a range of behaviors in these mouse models.
This study aims to fill a deficit in terms of a lack of targeted strategies for the synaptic risk pathway in ASD. The proposed approach is based on an exquisitely selective manipulation and is supported by strong preliminary data. Validation of this approach will open the way for developing reagents targeting neurexin-1 as potential therapeutics, similar to modulators now used clinically for other disorders.