Dept. of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford CA 94305, USA.
Curr Opin Neurobiol. 2023 Aug;81:102727. doi: 10.1016/j.conb.2023.102727. Epub 2023 May 18.
Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for Cbln4). Classical studies demonstrated that neurexin-Cbln1-GluD2 complexes organize cerebellar parallel-fiber synapses, but the role of cerebellins outside of the cerebellum has only recently been clarified. In synapses of the hippocampal subiculum and prefrontal cortex, Nrxn1-Cbln2-GluD1 complexes strikingly upregulate postsynaptic NMDA-receptors, whereas Nrxn3-Cbln2-GluD1 complexes conversely downregulate postsynaptic AMPA-receptors. At perforant-path synapses in the dentate gyrus, in contrast, neurexin/Cbln4/Neogenin-1 complexes are essential for LTP without affecting basal synaptic transmission or NMDA- or AMPA-receptors. None of these signaling pathways are required for synapse formation. Thus, outside of the cerebellum neurexin/cerebellin complexes regulate synapse properties by activating specific downstream receptors.
脑蛋白聚糖（Cbln1-4）是一种分泌型衔接蛋白，可将突触前神经连接蛋白（Nrxn1-3）与突触后配体（Cbln1-3 的 GluD1/2 与 Cbln4 的 DCC 和 Neogenin-1）连接起来。经典研究表明，神经连接蛋白-Cbln1-GluD2 复合物可组织小脑平行纤维突触，但小脑蛋白聚糖在小脑外的作用直到最近才得到阐明。在海马下脚和前额叶皮质的突触中，Nrxn1-Cbln2-GluD1 复合物显著地上调突触后 NMDA 受体，而 Nrxn3-Cbln2-GluD1 复合物则相反地下调突触后 AMPA 受体。相比之下，在齿状回的穿通通路突触中，神经连接蛋白/Cbln4/Neogenin-1 复合物对于 LTP 是必需的，而不会影响基础突触传递或 NMDA 或 AMPA 受体。这些信号通路都不需要用于突触形成。因此，在小脑外，神经连接蛋白/脑蛋白聚糖复合物通过激活特定的下游受体来调节突触特性。
