Qin Liming, Liu Zhili, Guo Sile, Han Ying, Wang Xiankun, Ren Wen, Chen Jiewen, Zhen Hefu, Nie Chao, Xing Ke-Ke, Chen Tao, Südhof Thomas C, Sun Yuzhe, Zhang Bo
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
Mol Psychiatry. 2025 Jan;30(1):84-96. doi: 10.1038/s41380-024-02659-6. Epub 2024 Jul 13.
Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.
神经连接蛋白3（Nlgn3）是一种与自闭症相关的细胞粘附分子，它与神经配素相互作用，并在神经元和星形胶质细胞中均有大量表达。神经元Nlgn3是突触传递的重要调节因子，但星形胶质细胞Nlgn3的功能在很大程度上尚不清楚。鉴于Nlgn3突变在自闭症中的高外显率以及星形胶质细胞在神经精神疾病中日益凸显的作用，我们在此探讨星形胶质细胞Nlgn3是否可能像神经元Nlgn3一样塑造小脑的神经回路特性。对由CRISPR/Cas9介导的基因组编辑产生的标记Nlgn3蛋白进行成像显示，Nlgn3在小脑星形胶质细胞（伯格曼胶质细胞）的细胞体中富集，而在其精细突起中不富集。对Nlgn3进行星形胶质细胞特异性敲除后，未发现小鼠小脑中的突触数量、突触传递或星形胶质细胞形态有明显改变。然而，空间转录组分析显示，在敲除星形胶质细胞Nlgn3后，多种小脑细胞类型之间的基因表达发生了显著变化。因此，与神经元Nlgn3不同，小脑中的星形胶质细胞Nlgn3不参与突触的形成，但可能调节特定脑区的基因表达。
