Neuroligin-1 Signaling Controls LTP and NMDA Receptors by Distinct Molecular Pathways
Neuroligin-1 Signaling Controls LTP and NMDA Receptors by Distinct Molecular Pathways
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DOI：
10.1016/j.neuron.2019.02.013
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发表时间：
2019-05-08
期刊：
影响因子：
16.2
通讯作者：
Malenka, Robert C.
中科院分区：
文献类型：
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作者：
Wu, Xiaoting;Morishita, Wade K.;Malenka, Robert C.
神经胶素，突触后细胞粘附分子，与神经精神疾病，被广泛研究，但有关其功能的基本问题仍然存在。在四重条件基因敲除小鼠的所有neuroligins，以避免异源二聚化的文物，使用在体内的替代策略，我们表明，在海马CA 1区锥体神经元，neuroligin-1执行两个关键的功能，兴奋性突触由不同的分子机制。N-甲基-D-天冬氨酸（NMDA）受体依赖性LTP需要突触后神经连接素-1与突触前b-神经毒素的跨突触结合，但不需要神经连接素的胞质序列。相反，突触后NMDA受体（NMDAR）介导的反应涉及neurexin独立的机制，需要神经连接素-1的胞质序列。引人注目的是，神经连接素的缺失阻断了与LTP相关的脊柱扩张，如通过双光子成像监测的;这种阻断涉及与NMDAR依赖性LTP中神经连接素-1的作用相同的机制。我们的数据表明，neuroligin-1执行两个机制不同的信号功能和neuroligin-1介导的跨突触细胞粘附信号关键调节LTP。
Neuroligins, postsynaptic cell adhesion molecules that are linked to neuropsychiatric disorders, are extensively studied, but fundamental questions about their functions remain. Using in vivo replacement strategies in quadruple conditional knockout mice of all neuroligins to avoid heterodimerization artifacts, we show, in hippocampal CA1 pyramidal neurons, that neuroligin-1 performs two key functions in excitatory synapses by distinct molecular mechanisms. N-methyl-D-aspartate (NMDA) receptor-dependent LTP requires trans-synaptic binding of postsynaptic neuroligin-1 to presynaptic b-neurexins but not the cytoplasmic sequences of neuroligins. In contrast, postsynaptic NMDA receptor (NMDAR)-mediated responses involve a neurexin-independent mechanism that requires the neuroligin-1 cytoplasmic sequences. Strikingly, deletion of neuroligins blocked the spine expansion associated with LTP, as monitored by two-photon imaging; this block involved a mechanism identical to that of the role of neuroligin-1 in NMDAR-dependent LTP. Our data suggest that neuroligin-1 performs two mechanistically distinct signaling functions and that neurolign-1-mediated trans-synaptic cell adhesion signaling critically regulates LTP.