S-SCAM/MAGI-2 is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors.
S-SCAM/MAGI-2 is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors.
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DOI：
10.1523/jneurosci.0025-12.2012
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发表时间：
2012-05-16
期刊：
影响因子：
--
通讯作者：
Lee SH
中科院分区：
文献类型：
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作者：
Danielson E;Zhang N;Metallo J;Kaleka K;Shin SM;Gerges N;Lee SH
突触可塑性是学习和记忆的细胞基础，涉及AMPA受体（AMPAR）进出突触的动态运输。AMPAR运输的剩余关键未回答的方面之一是尽管蛋白质周转，突触强度仍被保留的机制。具体地，参与含GluA 2的AMPAR的维持的AMPAR支架分子的身份是完全未知的。在这里，我们报告，突触支架分子（S-SCAM，也称为膜相关鸟苷酸激酶倒置-2和萎缩蛋白相互作用蛋白-1）发挥维持突触强度的关键作用。大鼠海马神经元中S-SCAM水平的增加导致表面AMPAR水平的特异性增加，增强AMPAR介导的突触传递和树突棘的扩大，而不显著影响GluN水平或NMDAR EPSC。相反，通过RNA干扰介导的敲低降低S-SCAM水平导致突触AMPAR的丧失，随后是树突棘密度的严重降低。重要的是，S-SCAM调节突触AMPAR水平的方式，依赖于GluA 2而不是GluA 1，敏感的NSF相互作用，和独立的活动。此外，S-SCAM在不存在PSD-95的情况下增加表面AMPAR水平，而PSD-95依赖于S-SCAM来增加表面AMPAR水平。最后，S-SCAM过表达阻碍了NMDA诱导的AMPAR内化，并阻止了长期抑郁的诱导，而S-SCAM敲低并不影响长期抑郁。总之，这些结果表明，S-SCAM是一个必不可少的AMPAR支架分子的GluA 2-含有池的AMPAR，这是参与维持突触强度的组成性途径。
Synaptic plasticity, the cellular basis of learning and memory, involves the dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses. One of the remaining key unanswered aspects of AMPAR trafficking is the mechanism by which synaptic strength is preserved in spite of protein turnover. In particular, the identity of AMPAR scaffolding molecule(s) involved in the maintenance of GluA2-containing AMPARs is completely unknown. Here we report that Synaptic scaffolding molecule (S-SCAM, also called membrane-associated guanylate kinase inverted-2 and atrophin interacting protein-1) plays the critical role of maintaining synaptic strength. Increasing S-SCAM levels in rat hippocampal neurons led to specific increases in the surface AMPAR levels, enhanced AMPAR-mediated synaptic transmission, and enlargement of dendritic spines, without significantly effecting GluN levels or NMDAR EPSC. Conversely, decreasing S-SCAM levels by RNA interference-mediated knockdown caused the loss of synaptic AMPARs, which was followed by a severe reduction in the dendritic spine density. Importantly, S-SCAM regulated synaptic AMPAR levels in a manner, dependent on GluA2 not GluA1, sensitive to NSF interaction, and independent of activity. Further, S-SCAM increased surface AMPAR levels in the absence of PSD-95, while PSD-95 was dependent on S-SCAM to increase surface AMPAR levels. Finally, S-SCAM overexpression hampered NMDA-induced internalization of AMPARs and prevented the induction of long term depression, while S-SCAM knockdown did not affect long term depression. Together, these results suggest that S-SCAM is an essential AMPAR scaffolding molecule for the GluA2-containing pool of AMPARs, which are involved in the constitutive pathway of maintaining synaptic strength.