Tetratricopeptide repeat domain 9A modulates anxiety-like behavior in female mice
Tetratricopeptide repeat domain 9A modulates anxiety-like behavior in female mice
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DOI：
10.1038/srep37568
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发表时间：
2016-11-21
影响因子：
4.6
通讯作者：
Lin, Valerie Chun Ling
中科院分区：
文献类型：
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作者：
Lim, Lee Wei;Shrestha, Smeeta;Lin, Valerie Chun Ling
四肽重复结构域9A （TTC9A）在大脑中大量表达。以往对TTC9A敲除（TTC9A(-/-)）小鼠的研究表明，TTC9A负向调节雌激素的作用。本研究采用TTC9A（-/-）小鼠模型，通过TTC9A与雌激素的功能相互作用，探讨了TTC9A在焦虑样行为中的作用。对焦虑相关行为进行了一系列测试。我们的研究结果表明，与野生型TTC9A（+/+）小鼠相比，TTC9A（-/-）小鼠表现出焦虑样行为的增加。这种差异在卵巢切除术后消失，17- β -雌二醇苯甲酸酯（EB）在TTC9A（-/-）小鼠中恢复了这种升级的焦虑样行为。由于5-羟色胺被认为是焦虑行为的关键神经调节剂，我们测量了腹内侧前额叶皮层（vmPFC）和中脑背核（DRN）中色氨酸羟化酶（TPH） 1、TPH2（两者都参与5-羟色胺合成）和5-羟色胺转运蛋白（5-HTT）的mRNA水平。有趣的是，受EB影响的TTC9A（-/-）小鼠的焦虑加剧与EB在DRN中更大程度地诱导TPH 2和5-HTT是一致的，这些在情绪调节中起关键作用。综上所述，我们的数据表明TTC9A通过调节雌激素对DRN中血清素能系统的作用来调节焦虑相关行为。
Tetratricopeptide repeat domain 9A (TTC9A) expression is abundantly expressed in the brain. Previous studies in TTC9A knockout (TTC9A(-/-)) mice have indicated that TTC9A negatively regulates the action of estrogen. In this study we investigated the role of TTC9A on anxiety-like behavior through its functional interaction with estrogen using the TTC9A(-/-) mice model. A battery of tests on anxiety-related behaviors was conducted. Our results demonstrated that TTC9A(-/-) mice exhibited an increase in anxiety-like behaviors compared to the wild type TTC9A(+/+) mice. This difference was abolished after ovariectomy, and administration of 17-beta-estradiol benzoate (EB) restored this escalated anxiety-like behavior in TTC9A(-/-) mice. Since serotonin is well-known to be the key neuromodulator involved in anxiety behaviors, the mRNA levels of tryptophan hydroxylase (TPH) 1, TPH2 (both are involved in serotonin synthesis), and serotonin transporter (5-HTT) were measured in the ventromedial prefrontal cortex (vmPFC) and dorsal raphe nucleus (DRN). Interestingly, the heightened anxiety in TTC9A(-/-) mice under EB influence is consistent with a greater induction of TPH 2, and 5-HTT by EB in DRN that play key roles in emotion regulation. In conclusion, our data indicate that TTC9A modulates the anxiety-related behaviors through modulation of estrogen action on the serotonergic system in the DRN.