Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea.
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea.
Cell Rep. 2018 Jun 26;23(13):3839-3851. doi: 10.1016/j.celrep.2018.05.087.
Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4 mice) show suppressed N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4 mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders.
神经导向因子 G 配体 2（NGL-2）/LRRC4 与自闭症谱系障碍和精神分裂症有关，是一种富含亮氨酸重复的突触后黏附分子，它在细胞内与兴奋性突触后支架蛋白 PSD-95 相互作用，在突触间与突触前黏附分子神经导向因子 G2 相互作用。在功能上，NGL-2 调节兴奋性突触的发育和突触传递。然而，它是否调节突触可塑性和与疾病相关的特定行为尚不清楚。在这里，我们报告说，缺乏 NGL-2（Lrrc4 小鼠）的小鼠在海马体中表现出 N-甲基-D-天冬氨酸受体（NMDAR）依赖性突触可塑性受到抑制。NGL-2 通过 PSD-95 依赖和非依赖机制与 NMDAR 结合。此外，Lrrc4 小鼠表现出轻微的社交互动缺陷和重复行为，而 NMDA 受体的药理学激活可迅速改善这些行为。这些结果表明，NGL-2 促进 NMDAR 的突触稳定，调节 NMDAR 依赖性突触可塑性，并防止小鼠出现类似自闭症的行为，支持 NMDA 受体功能障碍导致自闭症谱系障碍的假说。
