Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.
Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.
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DOI：
10.7554/elife.71575
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发表时间：
2021-11-17
期刊：
影响因子：
7.7
通讯作者：
Perez-Otaño I
中科院分区：
文献类型：
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作者：
Conde-Dusman MJ;Dey PN;Elía-Zudaire Ó;Rabaneda LG;García-Lira C;Grand T;Briz V;Velasco ER;Andero R;Niñerola S;Barco A;Paoletti P;Wesseling JF;Gardoni F;Tavalin SJ;Perez-Otaño I
稳定记忆编码的突触修饰需要从头合成蛋白质。然而，神经元是高度分化的细胞，如何在突触水平上调节蛋白质合成尚不清楚。在这里，我们表征了由突触后支架 GIT1、雷帕霉素 (mTOR) 激酶的机制靶点和将突触刺激与 mTOR 依赖性蛋白质合成耦合的 Raptor 形成的神经元信号复合物；并鉴定出含有 GluN3A 亚基的 NMDA 受体作为 GIT1 与 mTOR 结合的关键负调节因子。通过增强 GluN3A 表达或沉默 GIT1 来破坏 GIT1/mTOR 复合物会抑制突触 mTOR 激活并限制特定活性调节 mRNA 的 mTOR 依赖性翻译。相反，GluN3A 的去除能够促进复合物的形成，增强 mTOR 依赖性蛋白质的合成，并促进小鼠联想记忆和空间记忆的巩固。通过轻度或间隔训练，记忆增强变得明显，可以通过在成年期间选择性地删除兴奋性神经元中的 GluN3A 来实现，并且不会损害认知的其他方面，例如记忆灵活性或消退。我们的研究结果提供了对突触翻译控制的机制见解，并揭示了认知增强的潜在选择性目标。
De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.