Alternative splicing and heparan sulfation converge on neurexin-1 to control glutamatergic transmission and autism-related behaviors
H. Peter Lu, Long Zuo, Kyle M. Roddick, Peng Zhang, Shinichiro Oku, Jessica F. Garden, Yuan Ge, Michael Bellefontaine, Mathias Delhaye, Richard E. Brown, Ann Marie Craig
Abstract
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.