CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors.
CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors.
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CREB 介导的突触发生和神经发生对于 5-HT1a 受体调节焦虑行为的作用至关重要
DOI：
10.1038/srep29551
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发表时间：
2016-07-12
影响因子：
4.6
通讯作者：
Zhu DY
中科院分区：
文献类型：
--
作者：
Zhang J;Cai CY;Wu HY;Zhu LJ;Luo CX;Zhu DY
5-羟色胺1a-受体（5-HT 1aR）与焦虑症的发病机制密切相关。然而，5-HT 1aR在焦虑中的作用机制仍然知之甚少。在这里，我们表明在小鼠海马中的转录因子cAMP反应元件结合蛋白（CREB）作为5-HT 1aR的效应物在调节焦虑相关行为中发挥作用。我们产生了重组慢病毒LV-CREB 133-GFP，表达显性阴性CREB，其不能在Ser 133处磷酸化以特异性降低CREB活性，以及表达组成型活性融合蛋白VP 16-CREB的LV-VP 16-CREB-GFP，其可以自身磷酸化以特异性增强CREB活性。LV-CREB 133-GFP可中和5-HT 1aR激动剂诱导的突触密度、棘密度、树突复杂性、神经发生以及突触素和亲棘素（两种特征性突触蛋白）表达的上调，并消除5-HT 1aR激动剂的抗焦虑作用;而LV-VP 16-CREB-GFP挽救了5-HT 1aR拮抗剂诱导的突触密度、棘密度、树突复杂性神经发生和突触素和spinophilin的表达，并逆转5-HT 1aR拮抗剂的致焦虑作用。通过辐射或敲低突触蛋白表达的突触发生的减少消除了CREB和5-HT 1aR激活的抗焦虑作用。这些发现表明，CREB介导的海马结构可塑性是至关重要的5-HT 1aR在调节焦虑相关行为的作用。
Serotonin 1a-receptor (5-HT1aR) has been specifically implicated in the pathogenesis of anxiety. However, the mechanism underlying the role of 5-HT1aR in anxiety remains poorly understood. Here we show in mice that the transcription factor cAMP response element binding protein (CREB) in the hippocampus functions as an effector of 5-HT1aR in modulating anxiety-related behaviors. We generated recombinant lentivirus LV-CREB133-GFP expressing a dominant negative CREB which could not be phosphorylated at Ser133 to specifically reduce CREB activity, and LV-VP16-CREB-GFP expressing a constitutively active fusion protein VP16-CREB which could be phosphorylated by itself to specifically enhance CREB activity. LV-CREB133-GFP neutralized 5-HT1aR agonist-induced up-regulation of synapse density, spine density, dendrite complexity, neurogenesis, and the expression of synapsin and spinophilin, two well-characterized synaptic proteins, and abolished the anxiolytic effect of 5-HT1aR agonist; whereas LV-VP16-CREB-GFP rescued the 5-HT1aR antagonist-induced down-regulation of synapse density, spine density, dendrite complexity, neurogenesis and synapsin and spinophilin expression, and reversed the anxiogenic effect of 5-HT1aR antagonist. The deletion of neurogenesis by irradiation or the diminution of synaptogenesis by knockdown of synapsin expression abolished the anxiolytic effects of both CREB and 5-HT1aR activation. These findings suggest that CREB-mediated hippoacampus structural plasticity is crucial for the role of 5-HT1aR in modulating anxiety-related behaviors.