Hippocampal Telomerase Is Involved in the Modulation of Depressive Behaviors
Hippocampal Telomerase Is Involved in the Modulation of Depressive Behaviors
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海马端粒酶参与抑郁行为的调节
DOI：
10.1523/jneurosci.0805-11.2011
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发表时间：
2011-08-24
影响因子：
5.3
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
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作者：
Zhou, Qi-Gang;Hu, Yao;Zhu, Dong-Ya
端粒和端粒酶的改变已被报道在情绪障碍。然而，端粒酶在抑郁症中的作用仍不清楚。在这里，我们表明，慢性轻度应激（CMS）导致海马端粒酶逆转录酶（TERT）水平和端粒酶活性的显着下降。抗抑郁药氟西汀可逆转CMS诱导的TERT和端粒酶活性变化。通过全身给药（100 mg · kg-1 · d-1，i. p.，海马内注射（0.7 μmol，2 μl）或微泵输注（0.134 μg/μl，0.25 μl/h）3′-叠氮脱氧胸苷（AZT），可引起小鼠抑郁样行为和海马神经发生障碍。相反，通过海马内输注表达小鼠TERT的重组腺病毒载体（Ad-mTERT-GFP）过表达端粒酶导致神经发生上调，产生抗抑郁样行为，并阻止CMS诱导的行为改变。通过X射线照射（15戈伊）小鼠大脑中含有海马的限制区域来破坏齿状回的神经发生，消除了Ad-mTERT-GFP的抗抑郁样作用。此外，AZT对DNA聚合酶活性无影响，在体外和体内均未引起细胞损伤。侧脑室室管膜下区微量注射AZT（0.7 μmol，2 μl）可抑制局部神经发生，但对行为学无影响。这些结果表明，海马端粒酶参与抑郁相关行为的调制，可能通过调节成年神经发生。
Telomere and telomerase alterations have been reported in mood disorders. However, the role of telomerase in depression remains unclear. Here we show that chronic mild stress (CMS) led to a significant decrease in telomerase reverse transcriptase (TERT) level and telomerase activity in the hippocampus. Treatment with antidepressant fluoxetine reversed the CMS-induced TERT and telomerase activity changes. Inhibiting telomerase by systemic administration (100 mg · kg−1 · d−1, i.p., for 14 d), intrahippocampal microinjection (0.7 μmol, 2 μl), or infusion (using an osmotic minipump, 0.134 μg/μl, 0.25 μl/h) of 3′-azido-deoxythymidine (AZT) resulted in depression-like behaviors and impaired hippocampal neurogenesis in mice. In contrast, overexpressing telomerase by intrahippocampal infusion of recombinant adenovirus vector expressing mouse TERT (Ad-mTERT-GFP) led to neurogenesis upregulation, produced antidepressant-like behaviors, and prevented the CMS-induced behavioral modifications. Disrupting neurogenesis in the dentate gyrus by X-irradiation (15 Gy) of a restricted region of mouse brain containing the hippocampus abolished the antidepressant-like effect of Ad-mTERT-GFP. Additionally, AZT had no effect on DNA polymerase activity and did not cause cell damage in vitro and in vivo. Microinjection of AZT into the subventricular zone of lateral ventricle (0.7 μmol, 2 μl) inhibited local neurogenesis but had no behavioral effect. These results suggest that hippocampal telomerase is involved in the modulation of depression-related behaviors, possibly by regulating adult neurogenesis.