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Zuo, Long

University of British Columbia

Neurons communicate using a specialized junction called the synapse, whose properties are regulated by synaptic organizing molecules. Neurexin is one of the most studied synaptic organizers and is critical for both inhibitory and excitatory synaptic transmission and mouse survival. NRXN1 encoding one of three neurexin proteins is amongst the strongest risk genes for schizophrenia, Tourette’s Syndrome, and autism spectrum disorder (ASD). Neurexin-1 organizes the synapse by interacting with distinct postsynaptic ligands, many of which are themselves important for synaptic development. Neurexin-1 generates 3 forms from 3 promoters, all of which undergo heparan sulfate (HS) modification, a rare glycan modification essential for normal neurexin-ligand interaction. Six alternative splice sites (S1-S6) further diversify neurexin-1 structure. The most studied S4 modulates specific neurexin-ligand interactions to shape transmission and behavior in mice. Little is known, however, about S5 present in all three forms of neurexin-1 or the relationship between alternative splicing and HS modification. An understanding of these regulatory mechanisms might offer insights for developing therapeutic strategies. In chapter 2, we report a novel mechanism in which neurexin-1 S5 and HS modification jointly fine-tune synaptic transmission. When included, S5 confers a three-residue sequence that increases the number of HS chains. This is accompanied by reductions in neurexin-1 protein level and glutamatergic transmission but no change in binding affinities with canonical postsynaptic ligands. Conversely, mice in which neurexin-1 was engineered to lack S5 showed boosted synaptic neurotransmitter release without changes in postsynaptic receptor ratios. These mice were also behaviorally shifted away from phenotypes associated with ASD. While NRXN1 heterozygous deletion is frequently observed in ASD patients, functional and mechanistic studies have been limited, restricting the development of effective therapeutic strategies. Therefore, we generated mice with heterozygous loss of Nrxn1 and characterized deficits in neurexin-1 protein level and synaptic transmission. We then engineered the remaining Nrxn1 allele to lack S5 and observed alleviation of deficits due to neurexin-1 haploinsufficiency. In chapter 4, we discuss future experiments for a clearer mechanistic understanding of neurexin-1 regulation and how to combine the present discovery with existing technology to develop therapeutic strategies for deficits associated with NRXN1 deletion in patients.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83790

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/