| First Author | Lu H | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 7 | Pages | 112714 |
| PubMed ID | 37384525 | Mgi Jnum | J:338373 |
| Mgi Id | MGI:7511307 | Doi | 10.1016/j.celrep.2023.112714 |
| Citation | Lu H, et al. (2023) Alternative splicing and heparan sulfation converge on neurexin-1 to control glutamatergic transmission and autism-related behaviors. Cell Rep 42(7):112714 |
| abstractText | Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain, with over a thousand alternatively spliced forms and further structural heterogeneity contributed by heparan sulfate glycan modification. Yet, interactions between these modes of post-transcriptional and post-translational modification have not been studied. We reveal that these regulatory modes converge on neurexin-1 splice site 5 (S5): the S5 insert increases the number of heparan sulfate chains. This is associated with reduced neurexin-1 protein level and reduced glutamatergic neurotransmitter release. Exclusion of neurexin-1 S5 in mice boosts neurotransmission without altering the AMPA/NMDA ratio and shifts communication and repetitive behavior away from phenotypes associated with autism spectrum disorders. Thus, neurexin-1 S5 acts as a synaptic rheostat to impact behavior through the intersection of RNA processing and glycobiology. These findings position NRXN1 S5 as a potential therapeutic target to restore function in neuropsychiatric disorders. |
