S-SCAM inhibits Axin-dependent synaptic function of GSK3β in a sex-dependent manner.
S-SCAM inhibits Axin-dependent synaptic function of GSK3β in a sex-dependent manner.
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DOI：
10.1038/s41598-022-08220-1
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发表时间：
2022-03-08
影响因子：
4.6
通讯作者：
Lee SH
中科院分区：
文献类型：
--
作者：
Kearney G;Grau D;Nieves Torres D;Shin SM;Lee SH
S-SCAM/MAGI-2基因重复与精神分裂症相关。在转基因(TG)小鼠模型中，S-SCAM在前脑的过表达诱导了SCZ样表型。有趣的是，S-SCAM转基因小鼠在突触可塑性和工作记忆方面显示出男性特有的损害。然而，性别缺陷的潜在机制仍然不清楚。在此，我们报道了S-SCAM TG小鼠在突触GSK3β功能上存在雄性特异性缺陷，表现为突触蛋白水平降低和GSK3β抑制磷酸化增加。这种GSK3CaMKIIβ的过度磷酸化与CaMKII活性的增加有关。值得注意的是，在雄性S-SCAM TG小鼠中，GSK3β与S-SCAM竞争结合到的Axin1的突触水平也降低了。我们证明轴突蛋白结合是S-SCAM过度表达诱导突触GSK3β减少所必需的。用XAV939稳定轴突，可挽救S-SCAM高表达神经元在长期抑郁状态下GSK3β的缺失，并恢复β的短暂激活。有趣的是，在雌性S-SCAM TG小鼠中，突触Axin2水平增加。雌性激素17β-雌二醇增加S-SCAM高表达神经元Axin2的表达，增加突触GSK3β的水平。这些结果揭示了S-SCAM在控制GSK3β轴突依赖突触定位中的作用。此外，我们的研究指出了在人类中发现的GSK3β功能低下的病理相关性，并有助于理解SCZ性别差异的分子基础。
S-SCAM/MAGI-2 gene duplication is associated with schizophrenia (SCZ). S-SCAM overexpression in the forebrain induces SCZ-like phenotypes in a transgenic (Tg) mouse model. Interestingly, S-SCAM Tg mice show male-specific impairments in synaptic plasticity and working memory. However, mechanisms underlying the sex-specific deficits remain unknown. Here we report that S-SCAM Tg mice have male-specific deficits in synaptic GSK3β functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3β. This GSK3β hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3β binds in competition with S-SCAM, were also reduced in male S-SCAM Tg mice. We demonstrated that Axin-binding is required for the S-SCAM overexpression-induced synaptic GSK3β reduction. Axin stabilization using XAV939 rescued the GSK3β deficits and restored the temporal activation of GSK3β during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17β-estradiol increased Axin2 expression and increased synaptic GSK3β levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3β. Moreover, our studies point out the pathological relevance of GSK3β hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ.
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影响因子：
34.7
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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