Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses
Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses
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DOI：
10.1523/jneurosci.1702-04.2004
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发表时间：
2004-10-20
影响因子：
5.3
通讯作者：
Schachner, M
中科院分区：
文献类型：
--
作者：
Dityatev, A;Dityateva, G;Schachner, M
神经细胞粘附分子（NCAM）的表达在早期突触形成过程中促进了突触的长期增强（LTP）和稳定。在这里，我们寻找NCAM突触形成活性的机制，重点关注聚唾液酸（PSA）的作用，这是一种与NCAM优先相关的不寻常的碳水化合物。我们发现，在野生型和缺乏ncam的海马神经元异种型共培养中，用内神经氨酸酶- n （endon - n）去除PSA可以消除ncam表达细胞上突触的优先形成。转染三种主要的NCAM亚型（胞内结构域不同，胞外结构域相同，并携带PSA）中的任何一种NCAM缺陷神经元，都会刺激表达NCAM亚型的神经元上的优先突触形成。从培养的神经元中去除硫酸肝素和NCAM的肝素结合区域的突变会降低神经元表达的PSA-NCAM的突触形成活性，这表明NCAM与硫酸肝素蛋白聚糖的相互作用介导了这种活性。psa - ncam驱动的突触发生也被成纤维细胞生长因子受体和谷氨酸受体的NMDA亚型拮抗剂阻断，但不被非NMDA谷氨酸受体和电压依赖性Na+通道的阻滞剂阻断。酶法去除PSA和硫酸肝素也阻断了器官型海马CA1区与NMDA受体依赖性LTP相关的穿孔棘突触数量的增加。因此，神经元PSA-NCAM与硫酸肝素蛋白聚糖复合物促进突触发生和突触活性依赖性重构。
Expression of the neural cell adhesion molecule ( NCAM) has been shown to promote long-term potentiation (LTP) and stabilization of synapses during early synaptogenesis. Here, we searched for the mechanisms of synaptogenic activity of NCAM, focusing on the role of polysialic acid (PSA), an unusual carbohydrate preferentially associated with NCAM. We show that enzymatic removal of PSA with endoneuraminidase-N (endo-N) abolished preferential formation of synapses on NCAM-expressing cells in heterogenotypic cocultures of wild-type and NCAM-deficient hippocampal neurons. Transfection of NCAM-deficient neurons with either of three major NCAM isoforms ( different in intracellular domains but identical in extracellular domains and carrying PSA) stimulated preferential synapse formation on NCAM isoform-expressing neurons. Enzymatic removal of heparan sulfates from cultured neurons and a mutation in the heparin-binding domain of NCAM diminished synaptogenic activity of neuronally expressed PSA-NCAM, suggesting that interaction of NCAM with heparan sulfate proteoglycans mediates this activity. PSA-NCAM-driven synaptogenesis was also blocked by antagonists to fibroblast growth factor receptor and NMDA subtype of glutamate receptors but not by blockers of non-NMDA glutamate receptors and voltage-dependent Na+ channels. Enzymatic removal of PSA and heparan sulfates also blocked the increase in the number of perforated spine synapses associated with NMDA receptor-dependent LTP in the CA1 region of organotypic hippocampal cultures. Thus, neuronal PSA-NCAM in complex with heparan sulfate proteoglycans promotes synaptogenesis and activity-dependent remodeling of synapses.