Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength
Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength
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DOI：
10.1523/jneurosci.0116-16.2016
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发表时间：
2016-08-31
影响因子：
5.3
通讯作者：
Garner, Craig C.
中科院分区：
文献类型：
--
作者：
Arons, Magali H.;Lee, Kevin;Garner, Craig C.
Shank3 是一种多结构域支架蛋白，定位于兴奋性突触的突触后密度。体内和体外的功能研究支持这样的概念：Shank3 对于突触可塑性以及突触前神经递质释放的可靠性和突触后反应性之间的跨突触耦合至关重要。然而，Shank3 如何调节突触强度仍不清楚。 Shank3 的 C 末端包含一个无菌 α 基序 (SAM) 结构域，该结构域对于其突触后定位至关重要，并且还结合锌，因此增加了改变锌水平调节树突棘中 Shank3 功能的可能性。为了支持这一假设，我们发现锌是大鼠海马神经元 Shank3 激活和动力学的有效调节剂。此外，我们发现锌对突触传递的调节是 Shank3 依赖性的。有趣的是，Shank3 的自闭症谱系障碍 (ASD) 相关变体 (Shank3R87C) 保留了其锌敏感性，并支持 AMPAR 介导的突触传递的锌依赖性激活。然而，升高的锌无法挽救由 R87C 突变引起的跨突触信号传导缺陷，这意味着神经递质释放的跨突触增加对于锌的突触后作用并不是必需的。总之，这些数据表明 Shank3 是锌敏感信号系统的关键组成部分，调节自闭症谱系障碍中可能受损的突触强度。
Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3 (Shank3R87C) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD.