The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65
The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65
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GluA1 的氨基末端结构域通过与 Neuroplastin-65 相互作用介导 LTP 维持
DOI：
10.1073/pnas.2019194118
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发表时间：
2021-03-02
影响因子：
11.1
通讯作者：
Shi, Yun Stone
中科院分区：
文献类型：
--
作者：
Jiang, Chao-Hua;Wei, Mengping;Shi, Yun Stone
意义 长时程增强 (LTP) 是神经元之间在强烈刺激下增强的通讯，是学习和记忆的重要细胞机制。从机制上讲，LTP 表达涉及 AMPA 型谷氨酸受体插入突触（起始）并在突触处停留较长时间（维持）。在这里，我们发现 AMPA 受体亚基 GluA1 的氨基末端结构域选择性地与粘附蛋白 Np65 相互作用，这种相互作用是 LTP 期间 AMPA 受体突触锚定所必需的。我们的研究揭示了 GluA1 依赖性 LTP 维持的分子机制。长时程增强（LTP）长期以来一直被认为是学习和记忆的重要细胞机制。 LTP 表达涉及 AMPA 受体 (AMPAR) 的 NMDA 受体依赖性突触插入。然而，在 LTP 期间 AMPAR 如何被招募并锚定在突触后膜上仍然很大程度上未知。在这项研究中，我们使用CRISPR/Cas9删除内源性AMPAR并用单个神经元中的突变形式替换它们，我们发现GluA1的氨基末端结构域（ATD）是LTP维持所必需的。此外，我们发现 GluA1 ATD 直接与细胞粘附分子 Neuroplastin-65 (Np65) 相互作用。缺乏 Np65 的神经元表现出严重受损的 LTP 维持，而 Np65 缺失会阻止 GluA1 在 AMPAR 缺失的神经元中拯救 LTP。因此，我们的研究揭示了 LTP 期间 GluA1/Np65 结合在将 AMPAR 锚定在突触后膜上的重要作用。
Significance Long-term potentiation (LTP), the communication between neurons that is potentiated upon strong stimulus, is an important cellular mechanism underlying learning and memory. Mechanistically, LTP expression involves AMPA-type glutamate receptors insertion into synapses (initiation) and trapped at the synapses for an extended period of time (maintenance). Here, we show that the amino-terminal domain of GluA1, a subunit of AMPA receptors, selectively interacts with the adhesion protein Np65, and this interaction is required for the synaptic anchoring of AMPA receptors during LTP. Our study reveals a molecular mechanism underlying GluA1-dependent LTP maintenance. Long-term potentiation (LTP) has long been considered as an important cellular mechanism for learning and memory. LTP expression involves NMDA receptor-dependent synaptic insertion of AMPA receptors (AMPARs). However, how AMPARs are recruited and anchored at the postsynaptic membrane during LTP remains largely unknown. In this study, using CRISPR/Cas9 to delete the endogenous AMPARs and replace them with the mutant forms in single neurons, we have found that the amino-terminal domain (ATD) of GluA1 is required for LTP maintenance. Moreover, we show that GluA1 ATD directly interacts with the cell adhesion molecule neuroplastin-65 (Np65). Neurons lacking Np65 exhibit severely impaired LTP maintenance, and Np65 deletion prevents GluA1 from rescuing LTP in AMPARs-deleted neurons. Thus, our study reveals an essential role for GluA1/Np65 binding in anchoring AMPARs at the postsynaptic membrane during LTP.