The involvement of tetratricopeptide repeat domain 9A (TTC9A) deficiency in anxiety-like responses and behavioral despair through estradiol action on the serotonergic system has been reported. Emerging evidence suggests that estradiol is a potent modulator of neuroplasticity. As estradiol and neuroplasticity changes are both implicated in mood regulation, and estradiol activity is negatively regulated by TTC9A, we hypothesized that the behavioral changes induced by Ttc9a-/- is also mediated by neuroplasticity-related mechanisms. To understand the effects of TTC9A and estradiol modulation on neuroplasticity functions, we performed a behavioral analysis of tail suspension immobility and neuroplasticity-related gene expression study of brain samples collected in a previous study involving ovariectomized (OVX) Ttc9a-/- mice with estradiol or vehicle treatment. We observed that OVX-Ttc9a-/- mice had significantly reduced the tail suspension immobility compared to OVX-Ttc9a-/- estradiol-treated mice. Interestingly, there was an upregulation in gene expression of tropomyosin receptor kinase B (Trkb) in the ventral hippocampus, as well as brain-derived neurotrophic factor (Bdnf) and postsynaptic density protein-95 (Psd-95) in the amygdala of OVX-Ttc9a-/- mice compared to those treated with estradiol. These findings indicate that estradiol plays an inhibitory role in neuroplasticity in Ttc9a-/- mice. These observations were not found in the wildtype mice, as the presence of TTC9A suppressed the effects of estradiol. Our data suggest the behavioral alterations in Ttc9a-/- mice were mediated by estradiol regulation involving neuroplasticity-related mechanisms in both the hippocampus and amygdala regions.

中文翻译：

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TTC9A 缺乏诱导雌性小鼠海马和杏仁核神经可塑性相关基因表达的雌二醇介导的变化。

据报道，四三肽重复结构域 9A (TTC9A) 缺陷通过雌二醇对 5-羟色胺能系统的作用而参与焦虑样反应和行为绝望。新出现的证据表明雌二醇是一种有效的神经可塑性调节剂。由于雌二醇和神经可塑性变化都与情绪调节有关，而雌二醇活性受 TTC9A 负调节，我们假设 Ttc9a-/- 诱导的行为变化也由神经可塑性相关机制介导。为了了解 TTC9A 和雌二醇调节对神经可塑性功能的影响，我们对先前研究中收集的脑样本进行了尾悬不动和神经可塑性相关基因表达的行为分析，该研究涉及使用雌二醇或载体治疗的卵巢切除 (OVX) Ttc9a-/- 小鼠。我们观察到，与 OVX-Ttc9a-/- 雌二醇处理的小鼠相比，OVX-Ttc9a-/- 小鼠的尾部悬垂不动性显着降低。有趣的是，腹侧海马中原肌球蛋白受体激酶 B (Trkb) 以及 OVX 杏仁核中脑源性神经营养因子 (Bdnf) 和突触后密度蛋白 95 (Psd-95) 的基因表达上调 - Ttc9a-/- 小鼠与雌二醇治疗的小鼠相比。这些发现表明雌二醇在 Ttc9a-/- 小鼠的神经可塑性中起抑制作用。在野生型小鼠中没有发现这些观察结果，因为 TTC9A 的存在抑制了雌二醇的作用。我们的数据表明 Ttc9a-/- 小鼠的行为改变是由雌二醇调节介导的，涉及海马和杏仁核区域的神经可塑性相关机制。