Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, Japan.
Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
Nat Commun. 2021 Mar 23;12(1):1848. doi: 10.1038/s41467-021-22059-6.
Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.
神经黏附素 3（NLGN3）和神经连接素（NRXNs）构成了经典的突触细胞黏附对，其与自闭症有关。在自闭症谱系障碍（ASD）中，社交能力可能受损。然而，NLGN3 介导的社交发育的分子机制尚不清楚。在这里，我们确定了 NLGN3 与蛋白酪氨酸磷酸酶 δ（PTPδ）剪接变体之间的非经典相互作用，与 NRXN 结合竞争。NLGN3-PTPδ 复合物结构揭示了 PTPδ 和 NRXNs 之间的剪接依赖性相互作用模式和竞争机制。携带选择性损害 NLGN3-NRXN 相互作用的 NLGN3 突变的小鼠表现出更高的社交能力，而 NLGN3-PTPδ 相互作用受损的小鼠表现出社交行为受损和运动学习增强，兴奋性/抑制性突触蛋白表达失衡，正如 Nlgn3 R451C 自闭症模型所报道的那样。在神经元水平上，自闭症相关的 Nlgn3 R451C 突变导致非典型途径的选择性损伤。我们的发现表明，经典和非经典的 NLGN3 途径相互竞争并调节社交能力的发育。
