Background

Current antidepressants have limitations due to insufficient efficacy and delay before improvement in symptoms. Polymorphisms of the serotonin transporter (5-HTT) gene have been linked to depression (when combined with stressful life events) and altered response to selective serotonergic reuptake inhibitors. We have previously revealed the antidepressant-like properties of the iron chelator deferiprone in the 5-HTT knock-out (KO) mouse model of depression. Furthermore, deferiprone was found to alter neural activity in the prefrontal cortex of both wild-type (WT) and 5-HTT KO mice.

Methods

In the current study, we examined the molecular effects of acute deferiprone treatment in the prefrontal cortex of both genotypes via phosphoproteomics analysis.

Results

In WT mice treated with deferiprone, there were 22 differentially expressed phosphosites, with gene ontology analysis implicating cytoskeletal proteins. In 5-HTT KO mice treated with deferiprone, we found 33 differentially expressed phosphosites. Gene ontology analyses revealed phosphoproteins that were predominantly involved in synaptic and glutamatergic signalling. In a drug-naïve cohort (without deferiprone administration), the analysis revealed 21 differentially expressed phosphosites in 5-HTT KO compared to WT mice. We confirmed the deferiprone-induced increase in tyrosine hydroxylase serine 40 residue phosphorylation (pTH-Ser40) (initially revealed in our phosphoproteomics study) by Western blot analysis, with deferiprone increasing pTH-Ser40 expression in WT and 5-HTT KO mice.

Conclusion

As glutamatergic and synaptic signalling are dysfunctional in 5-HTT KO mice (and are the target of fast-acting antidepressant drugs such as ketamine), these molecular effects may underpin deferiprone's antidepressant-like properties. Furthermore, dopaminergic signalling may also be involved in deferiprone's antidepressant-like properties.

中文翻译：

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磷酸蛋白质组学表明谷氨酸能和多巴胺能信号传导与铁螯合剂去铁酮的抗抑郁样特性有关

背景

目前的抗抑郁药物由于疗效不足且症状改善延迟而存在局限性。血清素转运蛋白 (5-HTT) 基因的多态性与抑郁症（当与压力性生活事件结合时）以及对选择性血清素再摄取抑制剂的反应改变有关。我们之前已经揭示了铁螯合剂去铁酮在 5-HTT 敲除 (KO) 小鼠抑郁模型中的抗抑郁样特性。此外，还发现去铁酮可以改变野生型 (WT) 和 5-HTT KO 小鼠前额皮质的神经活动。

方法

在当前的研究中，我们通过磷酸蛋白质组学分析检查了急性去铁酮治疗对两种基因型前额皮质的分子效应。

结果

在用去铁酮治疗的 WT 小鼠中，有 22 个差异表达的磷酸位点，基因本体分析表明细胞骨架蛋白。在用去铁酮治疗的 5-HTT KO 小鼠中，我们发现了 33 个差异表达的磷酸位点。基因本体分析揭示了主要参与突触和谷氨酸信号传导的磷蛋白。在未接受药物治疗的队列中（未给予去铁酮），分析显示与 WT 小鼠相比，5-HTT KO 小鼠中有 21 个差异表达的磷酸位点。我们通过蛋白质印迹分析证实了去铁酮诱导的酪氨酸羟化酶丝氨酸40 残基磷酸化 (pTH-Ser40) 的增加（最初在我们的磷酸蛋白质组学研究中揭示），去铁酮增加了 WT 和 5-HTT KO 小鼠中的 pTH-Ser40 表达。

结论

由于 5-HTT KO 小鼠的谷氨酸能和突触信号传导功能失调（并且是氯胺酮等速效抗抑郁药物的目标），因此这些分子效应可能支撑去铁酮的抗抑郁样特性。此外，多巴胺能信号传导也可能与去铁酮的抗抑郁样特性有关。